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Wikipedia

Ubiquitin

August 16, 2023

Not to be confused with Ubiquinol.

Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975[1] by Gideon Goldstein and further characterized throughout the late 1970s and 1980s.[2] Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.[3]

Ubiquitin family
A diagram of ubiquitin. The seven lysine sidechains are shown in yellow/orange.
Identifiers
Symbolubiquitin
PfamPF00240
InterProIPR000626
PROSITEPDOC00271
SCOP21aar / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

The addition of ubiquitin to a substrate protein is called ubiquitylation (or, alternatively, ubiquitination or ubiquitinylation). Ubiquitylation affects proteins in many ways: it can mark them for degradation via the proteasome, alter their cellular location, affect their activity, and promote or prevent protein interactions.[4][5][6] Ubiquitylation involves three main steps: activation, conjugation, and ligation, performed by ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s), respectively. The result of this sequential cascade is to bind ubiquitin to lysine residues on the protein substrate via an isopeptide bond, cysteine residues through a thioester bond, serine and threonine residues through an ester bond, or the amino group of the protein's N-terminus via a peptide bond.[7][8][9]

The protein modifications can be either a single ubiquitin protein (monoubiquitylation) or a chain of ubiquitin (polyubiquitylation). Secondary ubiquitin molecules are always linked to one of the seven lysine residues or the N-terminal methionine of the previous ubiquitin molecule. These 'linking' residues are represented by a "K" or "M" (the one-letter amino acid notation of lysine and methionine, respectively) and a number, referring to its position in the ubiquitin molecule as in K48, K29 or M1. The first ubiquitin molecule is covalently bound through its C-terminal carboxylate group to a particular lysine, cysteine, serine, threonine or N-terminus of the target protein. Polyubiquitylation occurs when the C-terminus of another ubiquitin is linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule, creating a chain. This process repeats several times, leading to the addition of several ubiquitins. Only polyubiquitylation on defined lysines, mostly on K48 and K29, is related to degradation by the proteasome (referred to as the "molecular kiss of death"), while other polyubiquitylations (e.g. on K63, K11, K6 and M1) and monoubiquitylations may regulate processes such as endocytic trafficking, inflammation, translation and DNA repair.[10]

The discovery that ubiquitin chains target proteins to the proteasome, which degrades and recycles proteins, was honored with the Nobel Prize in Chemistry in 2004.[8][11][12]

Identification

 
Surface representation of Ubiquitin.

Ubiquitin (originally, ubiquitous immunopoietic polypeptide) was first identified in 1975[1] as an 8.6 kDa protein expressed in all eukaryotic cells. The basic functions of ubiquitin and the components of the ubiquitylation pathway were elucidated in the early 1980s at the Technion by Aaron Ciechanover, Avram Hershko, and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004.[11]

The ubiquitylation system was initially characterised as an ATP-dependent proteolytic system present in cellular extracts. A heat-stable polypeptide present in these extracts, ATP-dependent proteolysis factor 1 (APF-1), was found to become covalently attached to the model protein substrate lysozyme in an ATP- and Mg2+-dependent process.[13] Multiple APF-1 molecules were linked to a single substrate molecule by an isopeptide linkage, and conjugates were found to be rapidly degraded with the release of free APF-1. Soon after APF-1-protein conjugation was characterised, APF-1 was identified as ubiquitin. The carboxyl group of the C-terminal glycine residue of ubiquitin (Gly76) was identified as the moiety conjugated to substrate lysine residues.

The protein

Ubiquitin properties (human)[which?]
Number of residues 76
Molecular mass 8564.8448 Da
Isoelectric point (pI) 6.79
Gene names RPS27A (UBA80, UBCEP1), UBA52 (UBCEP2), UBB, UBC
Sequence (single-letter)

MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPD

QQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG

Ubiquitin is a small protein that exists in all eukaryotic cells. It performs its myriad functions through conjugation to a large range of target proteins. A variety of different modifications can occur. The ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8.6 kDa. Key features include its C-terminal tail and the 7 lysine residues. It is highly conserved throughout eukaryote evolution; human and yeast ubiquitin share 96% sequence identity.[citation needed]

Genes

Ubiquitin is encoded in mammals by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. The UBB and UBC genes code for polyubiquitin precursor proteins.[3]

Ubiquitylation

 
The ubiquitylation system (showing a RING E3 ligase).

Ubiquitylation (also known as ubiquitination or ubiquitinylation) is an enzymatic post-translational modification in which a ubiquitin protein is attached to a substrate protein. This process most commonly binds the last amino acid of ubiquitin (glycine 76) to a lysine residue on the substrate. An isopeptide bond is formed between the carboxyl group (COO−) of the ubiquitin's glycine and the epsilon-amino group (ε-NH+
3) of the substrate's lysine.[14] Trypsin cleavage of a ubiquitin-conjugated substrate leaves a di-glycine "remnant" that is used to identify the site of ubiquitylation.[15][16] Ubiquitin can also be bound to other sites in a protein which are electron-rich nucleophiles, termed "non-canonical ubiquitylation".[9] This was first observed with the amine group of a protein's N-terminus being used for ubiquitylation, rather than a lysine residue, in the protein MyoD[17] and has been observed since in 22 other proteins in multiple species,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] including ubiquitin itself.[37][38] There is also increasing evidence for nonlysine residues as ubiquitylation targets using non-amine groups, such as the sulfhydryl group on cysteine,[33][34][39][40][41][42][43][44][45][46] and the hydroxyl group on threonine and serine.[33][34][39][45][46][47][48][49][50] The end result of this process is the addition of one ubiquitin molecule (monoubiquitylation) or a chain of ubiquitin molecules (polyubiquitination) to the substrate protein.[51]

Ubiquitination requires three types of enzyme: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases, known as E1s, E2s, and E3s, respectively. The process consists of three main steps:

  1. Activation: Ubiquitin is activated in a two-step reaction by an E1 ubiquitin-activating enzyme, which is dependent on ATP. The initial step involves production of a ubiquitin-adenylate intermediate. The E1 binds both ATP and ubiquitin and catalyses the acyl-adenylation of the C-terminus of the ubiquitin molecule. The second step transfers ubiquitin to an active site cysteine residue, with release of AMP. This step results in a thioester linkage between the C-terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group.[14][52] The human genome contains two genes that produce enzymes capable of activating ubiquitin: UBA1 and UBA6.[53]
  2. Conjugation: E2 ubiquitin-conjugating enzymes catalyse the transfer of ubiquitin from E1 to the active site cysteine of the E2 via a trans(thio)esterification reaction. In order to perform this reaction, the E2 binds to both activated ubiquitin and the E1 enzyme. Humans possess 35 different E2 enzymes, whereas other eukaryotic organisms have between 16 and 35. They are characterised by their highly conserved structure, known as the ubiquitin-conjugating catalytic (UBC) fold.[54]
     
    Glycine and lysine linked by an isopeptide bond. The isopeptide bond is highlighted yellow.
  3. Ligation: E3 ubiquitin ligases catalyse the final step of the ubiquitination cascade. Most commonly, they create an isopeptide bond between a lysine of the target protein and the C-terminal glycine of ubiquitin. In general, this step requires the activity of one of the hundreds of E3s. E3 enzymes function as the substrate recognition modules of the system and are capable of interaction with both E2 and substrate. Some E3 enzymes also activate the E2 enzymes. E3 enzymes possess one of two domains: the homologous to the E6-AP carboxyl terminus (HECT) domain and the really interesting new gene (RING) domain (or the closely related U-box domain). HECT domain E3s transiently bind ubiquitin in this process (an obligate thioester intermediate is formed with the active-site cysteine of the E3), whereas RING domain E3s catalyse the direct transfer from the E2 enzyme to the substrate.[55] The anaphase-promoting complex (APC) and the SCF complex (for Skp1-Cullin-F-box protein complex) are two examples of multi-subunit E3s involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome.[56]

In the ubiquitination cascade, E1 can bind with many E2s, which can bind with hundreds of E3s in a hierarchical way. Having levels within the cascade allows tight regulation of the ubiquitination machinery.[7] Other ubiquitin-like proteins (UBLs) are also modified via the E1–E2–E3 cascade, although variations in these systems do exist.[57]

E4 enzymes, or ubiquitin-chain elongation factors, are capable of adding pre-formed polyubiquitin chains to substrate proteins.[58] For example, multiple monoubiquitylation of the tumor suppressor p53 by Mdm2[59] can be followed by addition of a polyubiquitin chain using p300 and CBP.[60][61]

Types

See also: Ubiquitin ligase § Mono- and poly-ubiquitylation

Ubiquitination affects cellular process by regulating the degradation of proteins (via the proteasome and lysosome), coordinating the cellular localization of proteins, activating and inactivating proteins, and modulating protein–protein interactions.[4][5][6] These effects are mediated by different types of substrate ubiquitination, for example the addition of a single ubiquitin molecule (monoubiquitination) or different types of ubiquitin chains (polyubiquitination).[62]

Monoubiquitination

Monoubiquitination is the addition of one ubiquitin molecule to one substrate protein residue. Multi-monoubiquitination is the addition of one ubiquitin molecule to multiple substrate residues. The monoubiquitination of a protein can have different effects to the polyubiquitination of the same protein. The addition of a single ubiquitin molecule is thought to be required prior to the formation of polyubiquitin chains.[62] Monoubiquitination affects cellular processes such as membrane trafficking, endocytosis and viral budding.[10][63]

Polyubiquitin chains

 
Diagram of lysine 48-linked diubiquitin. The linkage between the two ubiquitin chains is shown in orange.
 
Diagram of lysine 63-linked diubiquitin. The linkage between the two ubiquitin chains is shown in orange.

Polyubiquitination is the formation of a ubiquitin chain on a single lysine residue on the substrate protein. Following addition of a single ubiquitin moiety to a protein substrate, further ubiquitin molecules can be added to the first, yielding a polyubiquitin chain.[62] These chains are made by linking the glycine residue of a ubiquitin molecule to a lysine of ubiquitin bound to a substrate. Ubiquitin has seven lysine residues and an N-terminus that serves as points of ubiquitination; they are K6, K11, K27, K29, K33, K48, K63 and M1, respectively.[8] Lysine 48-linked chains were the first identified and are the best-characterised type of ubiquitin chain. K63 chains have also been well-characterised, whereas the function of other lysine chains, mixed chains, branched chains, M1-linked linear chains, and heterologous chains (mixtures of ubiquitin and other ubiquitin-like proteins) remains more unclear.[16][38][62][63][64]

Lysine 48-linked polyubiquitin chains target proteins for destruction, by a process known as proteolysis. Multi-ubiquitin chains at least four ubiquitin molecules long must be attached to a lysine residue on the condemned protein in order for it to be recognised by the 26S proteasome.[65] This is a barrel-shape structure comprising a central proteolytic core made of four ring structures, flanked by two cylinders that selectively allow entry of ubiquitinated proteins. Once inside, the proteins are rapidly degraded into small peptides (usually 3–25 amino acid residues in length). Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use.[66] Although the majority of protein substrates are ubiquitinated, there are examples of non-ubiquitinated proteins targeted to the proteasome.[67] The polyubiquitin chains are recognised by a subunit of the proteasome: S5a/Rpn10. This is achieved by a ubiquitin-interacting motif (UIM) found in a hydrophobic patch in the C-terminal region of the S5a/Rpn10 unit.[4]

Lysine 63-linked chains are not associated with proteasomal degradation of the substrate protein. Instead, they allow the coordination of other processes such as endocytic trafficking, inflammation, translation, and DNA repair.[10] In cells, lysine 63-linked chains are bound by the ESCRT-0 complex, which prevents their binding to the proteasome. This complex contains two proteins, Hrs and STAM1, that contain a UIM, which allows it to bind to lysine 63-linked chains.[68][69]

Methionine 1-linked (or linear) polyubiquitin chains are another type of non-degradative ubiquitin chains. In this case, ubiquitin is linked in a head-to-tail manner, meaning that the C-terminus of the last ubiquitin molecule binds directly to the N-terminus of the next one. Although initially believed to target proteins for proteasomal degradation,[70] linear ubiquitin later proved to be indispensable for NF-kB signaling.[71] Currently, there is only one known E3 ubiquitin ligase generating M1-linked polyubiquitin chains - linear ubiquitin chain assembly complex (LUBAC).[38][72]

Less is understood about atypical (non-lysine 48-linked) ubiquitin chains but research is starting to suggest roles for these chains.[63] There is evidence to suggest that atypical chains linked by lysine 6, 11, 27, 29 and methionine 1 can induce proteasomal degradation.[67][73]

Branched ubiquitin chains containing multiple linkage types can be formed.[74] The function of these chains is unknown.[8]

Structure

Differently linked chains have specific effects on the protein to which they are attached, caused by differences in the conformations of the protein chains. K29-, K33-,[75] K63- and M1-linked chains have a fairly linear conformation; they are known as open-conformation chains. K6-, K11-, and K48-linked chains form closed conformations. The ubiquitin molecules in open-conformation chains do not interact with each other, except for the covalent isopeptide bonds linking them together. In contrast, the closed conformation chains have interfaces with interacting residues. Altering the chain conformations exposes and conceals different parts of the ubiquitin protein, and the different linkages are recognized by proteins that are specific for the unique topologies that are intrinsic to the linkage. Proteins can specifically bind to ubiquitin via ubiquitin-binding domains (UBDs). The distances between individual ubiquitin units in chains differ between lysine 63- and 48-linked chains. The UBDs exploit this by having small spacers between ubiquitin-interacting motifs that bind lysine 48-linked chains (compact ubiquitin chains) and larger spacers for lysine 63-linked chains. The machinery involved in recognising polyubiquitin chains can also differentiate between K63-linked chains and M1-linked chains, demonstrated by the fact that the latter can induce proteasomal degradation of the substrate.[8][10][73]

Function

The ubiquitination system functions in a wide variety of cellular processes, including:[76]

Membrane proteins

Multi-monoubiquitination can mark transmembrane proteins (for example, receptors) for removal from membranes (internalisation) and fulfil several signalling roles within the cell. When cell-surface transmembrane molecules are tagged with ubiquitin, the subcellular localization of the protein is altered, often targeting the protein for destruction in lysosomes. This serves as a negative feedback mechanism, because often the stimulation of receptors by ligands increases their rate of ubiquitination and internalisation. Like monoubiquitination, lysine 63-linked polyubiquitin chains also has a role in the trafficking some membrane proteins.[10][62][65][78]

Genomic maintenance

Proliferating cell nuclear antigen (PCNA) is a protein involved in DNA synthesis. Under normal physiological conditions PCNA is sumoylated (a similar post-translational modification to ubiquitination). When DNA is damaged by ultra-violet radiation or chemicals, the SUMO molecule that is attached to a lysine residue is replaced by ubiquitin. Monoubiquitinated PCNA recruits polymerases that can carry out DNA synthesis with damaged DNA; but this is very error-prone, possibly resulting in the synthesis of mutated DNA. Lysine 63-linked polyubiquitination of PCNA allows it to perform a less error-prone mutation bypass known by the template switching pathway.[6][79][80]

Ubiquitination of histone H2AX is involved in DNA damage recognition of DNA double-strand breaks. Lysine 63-linked polyubiquitin chains are formed on H2AX histone by the E2/E3 ligase pair, Ubc13-Mms2/RNF168.[81][82] This K63 chain appears to recruit RAP80, which contains a UIM, and RAP80 then helps localize BRCA1. This pathway will eventually recruit the necessary proteins for homologous recombination repair.[83]

Transcriptional regulation

Histones can be ubiquitinated and this is usually in the form of monoubiquitination (although polyubiquitinated forms do occur). Histone ubiquitination alters chromatin structure and allows the access of enzymes involved in transcription. Ubiquitin on histones also acts as a binding site for proteins that either activate or inhibit transcription and also can induce further post-translational modifications of the protein. These effects can all modulate the transcription of genes.[84][85]

Deubiquitination

Deubiquitinating enzymes (DUBs) oppose the role of ubiquination by removing ubiquitin from substrate proteins. They are cysteine proteases that cleave the amide bond between the two proteins. They are highly specific, as are the E3 ligases that attach the ubiquitin, with only a few substrates per enzyme. They can cleave both isopeptide (between ubiquitin and lysine) and peptide bonds (between ubiquitin and the N-terminus). In addition to removing ubiquitin from substrate proteins, DUBs have many other roles within the cell. Ubiquitin is either expressed as multiple copies joined in a chain (polyubiquitin) or attached to ribosomal subunits. DUBs cleave these proteins to produce active ubiquitin. They also recycle ubiquitin that has been bound to small nucleophilic molecules during the ubiquitination process. Monoubiquitin is formed by DUBs that cleave ubiquitin from free polyubiquitin chains that have been previously removed from proteins.[86][87]

Ubiquitin-binding domains

Table of characterized Ubiquitin-binding domains[88]
Domain Number of proteins

in proteome

Length

(amino acids)

Ubiquitin binding

Affinity

CUE S. cerevisiae: 7

H. sapiens: 21

42–43 ~2–160 μM
GATII S. cerevisiae: 2

H. sapiens: 14

135 ~180 μM
GLUE S. cerevisiae: ?

H. sapiens: ?

~135 ~460 μM
NZF S. cerevisiae: 1

H. sapiens: 25

~35 ~100–400 μM
PAZ S. cerevisiae: 5

H. sapiens: 16

~58 Not known
UBA S. cerevisiae: 10

H. sapiens: 98

45–55 ~0.03–500 μM
UEV S. cerevisiae: 2

H. sapiens: ?

~145 ~100–500 μM
UIM S. cerevisiae: 8

H. sapiens: 71

~20 ~100–400 μM
VHS S. cerevisiae: 4

H. sapiens: 28

150 Not known

Ubiquitin-binding domains (UBDs) are modular protein domains that non-covalently bind to ubiquitin, these motifs control various cellular events. Detailed molecular structures are known for a number of UBDs, binding specificity determines their mechanism of action and regulation, and how it regulates cellular proteins and processes.[88][89]

Disease associations

Pathogenesis

The ubiquitin pathway has been implicated in the pathogenesis of a wide range of diseases and disorders including:[90]

Neurodegeneration

Ubiquitin is implicated in neurodegenerative diseases associated with proteostasis dysfunction, including Alzheimer's disease, motor neuron disease,[91] Huntington's disease and Parkinson's disease.[90] Transcript variants encoding different isoforms of ubiquilin-1 are found in lesions associated with Alzheimer's and Parkinson's disease.[92] Higher levels of ubiquilin in the brain have been shown to decrease malformation of amyloid precursor protein (APP), which plays a key role in triggering Alzheimer's disease.[93] Conversely, lower levels of ubiquilin-1 in the brain have been associated with increased malformation of APP.[93] A frameshift mutation in ubiquitin B can result in a truncated peptide missing the C-terminal glycine. This abnormal peptide, known as UBB+1, has been shown to accumulate selectively in Alzheimer's disease and other tauopathies.

Infection and immunity

Ubiquitin and ubiquitin-like molecules extensively regulate immune signal transduction pathways at virtually all stages, including steady-state repression, activation during infection, and attenuation upon clearance. Without this regulation, immune activation against pathogens may be defective, resulting in chronic disease or death. Alternatively, the immune system may become hyperactivated and organs and tissues may be subjected to autoimmune damage.

On the other hand, viruses must block or redirect host cell processes including immunity to effectively replicate, yet many viruses relevant to disease have informationally limited genomes. Because of its very large number of roles in the cell, manipulating the ubiquitin system represents an efficient way for such viruses to block, subvert or redirect critical host cell processes to support their own replication.[94]

The retinoic acid-inducible gene I (RIG-I) protein is a primary immune system sensor for viral and other invasive RNA in human cells.[95] The RIG-I-like receptor (RLR) immune signaling pathway is one of the most extensively studied in terms of the role of ubiquitin in immune regulation.[96]

Genetic disorders

  • Angelman syndrome is caused by a disruption of UBE3A, which encodes a ubiquitin ligase (E3) enzyme termed E6-AP.
  • Von Hippel–Lindau syndrome involves disruption of a ubiquitin E3 ligase termed the VHL tumor suppressor, or VHL gene.
  • Fanconi anemia: Eight of the thirteen identified genes whose disruption can cause this disease encode proteins that form a large ubiquitin ligase (E3) complex.
  • 3-M syndrome is an autosomal-recessive growth retardation disorder associated with mutations of the Cullin7 E3 ubiquitin ligase.[97]

Diagnostic use

Immunohistochemistry using antibodies to ubiquitin can identify abnormal accumulations of this protein inside cells, indicating a disease process. These protein accumulations are referred to as inclusion bodies (which is a general term for any microscopically visible collection of abnormal material in a cell). Examples include:

Link to cancer

Post-translational modification of proteins is a generally used mechanism in eukaryotic cell signaling.[98] Ubiquitination, or ubiquitin conjugation to proteins, is a crucial process for cell cycle progression and cell proliferation and development. Although ubiquitination usually serves as a signal for protein degradation through the 26S proteasome, it could also serve for other fundamental cellular processes,[98] e.g. in endocytosis,[99] enzymatic activation[100] and DNA repair.[101] Moreover, since ubiquitination functions to tightly regulate the cellular level of cyclins, its misregulation is expected to have severe impacts. First evidence of the importance of the ubiquitin/proteasome pathway in oncogenic processes was observed due to the high antitumor activity of proteasome inhibitors.[102][103][104] Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or present in human carcinoma.[105][106][107][108][109][110][111][112] Malignancies could be developed through loss of function mutation directly at the tumor suppressor gene, increased activity of ubiquitination, and/or indirect attenuation of ubiquitination due to mutation in related proteins.[113]

Direct loss of function mutation of E3 ubiquitin ligase

Renal cell carcinoma

The VHL (Von Hippel–Lindau) gene encodes a component of an E3 ubiquitin ligase. VHL complex targets a member of the hypoxia-inducible transcription factor family (HIF) for degradation by interacting with the oxygen-dependent destruction domain under normoxic conditions. HIF activates downstream targets such as the vascular endothelial growth factor (VEGF), promoting angiogenesis. Mutations in VHL prevent degradation of HIF and thus lead to the formation of hypervascular lesions and renal tumors.[105][113]

Breast cancer

The BRCA1 gene is another tumor suppressor gene in humans which encodes the BRCA1 protein that is involved in response to DNA damage. The protein contains a RING motif with E3 Ubiquitin Ligase activity. BRCA1 could form dimer with other molecules, such as BARD1 and BAP1, for its ubiquitination activity. Mutations that affect the ligase function are often found and associated with various cancers.[109][113]

Cyclin E

As processes in cell cycle progression are the most fundamental processes for cellular growth and differentiation, and are the most common to be altered in human carcinomas, it is expected for cell cycle-regulatory proteins to be under tight regulation. The level of cyclins, as the name suggests, is high only at certain a time point during the cell cycle. This is achieved by continuous control of cyclins or CDKs levels through ubiquitination and degradation. When cyclin E is partnered with CDK2 and gets phosphorylated, an SCF-associated F-box protein Fbw7 recognizes the complex and thus targets it for degradation. Mutations in Fbw7 have been found in more than 30% of human tumors, characterizing it as a tumor suppressor protein.[112]

Increased ubiquitination activity

Cervical cancer

Oncogenic types of the human papillomavirus (HPV) are known to hijack cellular ubiquitin-proteasome pathway for viral infection and replication. The E6 proteins of HPV will bind to the N-terminus of the cellular E6-AP E3 ubiquitin ligase, redirecting the complex to bind p53, a well-known tumor suppressor gene whose inactivation is found in many types of cancer.[107] Thus, p53 undergoes ubiquitination and proteasome-mediated degradation. Meanwhile, E7, another one of the early-expressed HPV genes, will bind to Rb, also a tumor suppressor gene, mediating its degradation.[113] The loss of p53 and Rb in cells allows limitless cell proliferation to occur.

p53 regulation

Gene amplification often occur in various tumor cases, including of MDM2, a gene encodes for a RING E3 Ubiquitin ligase responsible for downregulation of p53 activity. MDM2 targets p53 for ubiquitination and proteasomal degradation thus keeping its level appropriate for normal cell condition. Overexpression of MDM2 causes loss of p53 activity and therefore allowing cells to have a limitless replicative potential.[108][113]

p27

Another gene that is a target of gene amplification is SKP2. SKP2 is an F-box protein with a role in substrate recognition for ubiquitination and degradation. SKP2 targets p27Kip-1, an inhibitor of cyclin-dependent kinases (CDKs). CDKs2/4 partner with the cyclins E/D, respectively, forming a family of cell cycle regulators which control cell cycle progression through the G1 phase. Low level of p27Kip-1 protein is often found in various cancers and is due to overactivation of ubiquitin-mediated proteolysis through overexpression of SKP2.[110][113]

Efp

Efp, or estrogen-inducible RING-finger protein, is an E3 ubiquitin ligase whose overexpression has been shown to be the major cause of estrogen-independent breast cancer.[104][114] Efp's substrate is 14-3-3 protein which negatively regulates cell cycle.

Evasion of ubiquitination

Colorectal cancer

The gene associated with colorectal cancer is the adenomatous polyposis coli (APC), which is a classic tumor suppressor gene. APC gene product targets beta-catenin for degradation via ubiquitination at the N-terminus, thus regulating its cellular level. Most colorectal cancer cases are found with mutations in the APC gene. However, in cases where APC gene is not mutated, mutations are found in the N-terminus of beta-catenin which renders it ubiquitination-free and thus increased activity.[106][113]

Glioblastoma

As the most aggressive cancer originated in the brain, mutations found in patients with glioblastoma are related to the deletion of a part of the extracellular domain of the epidermal growth factor receptor (EGFR). This deletion causes CBL E3 ligase unable to bind to the receptor for its recycling and degradation via a ubiquitin-lysosomal pathway. Thus, EGFR is constitutively active in the cell membrane and activates its downstream effectors that are involved in cell proliferation and migration.[111]

Phosphorylation-dependent ubiquitination

The interplay between ubiquitination and phosphorylation has been an ongoing research interest since phosphorylation often serves as a marker where ubiquitination leads to degradation.[98] Moreover, ubiquitination can also act to turn on/off the kinase activity of a protein.[115] The critical role of phosphorylation is largely underscored in the activation and removal of autoinhibition in the Cbl protein.[116] Cbl is an E3 ubiquitin ligase with a RING finger domain that interacts with its tyrosine kinase binding (TKB) domain, preventing interaction of the RING domain with an E2 ubiquitin-conjugating enzyme. This intramolecular interaction is an autoinhibition regulation that prevents its role as a negative regulator of various growth factors and tyrosine kinase signaling and T-cell activation.[116] Phosphorylation of Y363 relieves the autoinhibition and enhances binding to E2.[116] Mutations that render the Cbl protein dysfunctional due to the loss of its ligase/tumor suppressor function and maintenance of its positive signaling/oncogenic function have been shown to cause the development of cancer.[117][118]

As a drug target

Screening for ubiquitin ligase substrates

Deregulation of E3-substrate interactions is a key cause of many human disorders, therefore identifying E3 ligase substrates is crucial. In 2008, 'Global Protein Stability (GPS) Profiling' was developed to discover E3 ubiquitin ligase substrates.[119] This high-throughput system made use of reporter proteins fused with thousands of potential substrates independently. By inhibition of the ligase activity (through the making of Cul1 dominant negative thus renders ubiquitination not to occur), increased reporter activity shows that the identified substrates are being accumulated. This approach added a large number of new substrates to the list of E3 ligase substrates.

Possible therapeutic applications

Blocking of specific substrate recognition by the E3 ligases, e.g. bortezomib.[114]

Challenge

Finding a specific molecule that selectively inhibits the activity of a certain E3 ligase and/or the protein–protein interactions implicated in the disease remains as one of the important and expanding research area. Moreover, as ubiquitination is a multi-step process with various players and intermediate forms, consideration of the much complex interactions between components needs to be taken heavily into account while designing the small molecule inhibitors.[104]

Similar proteins

Main article: Ubiquitin-like protein

Ubiquitin is the most-understood post-translation modifier, however, several family of ubiquitin-like proteins (UBLs) are found can modify cellular targets in a parallel but distinct route. Known UBLs include: small ubiquitin-like modifier (SUMO), ubiquitin cross-reactive protein (UCRP, also known as interferon-stimulated gene-15 ISG15), ubiquitin-related modifier-1 (URM1), neuronal-precursor-cell-expressed developmentally downregulated protein-8 (NEDD8, also called Rub1 in S. cerevisiae), human leukocyte antigen F-associated (FAT10), autophagy-8 (ATG8) and -12 (ATG12), Few ubiquitin-like protein (FUB1), MUB (membrane-anchored UBL),[120] ubiquitin fold-modifier-1 (UFM1) and ubiquitin-like protein-5 (UBL5, which is but known as homologous to ubiquitin-1 [Hub1] in S. pombe).[121][122] Although these proteins share only modest primary sequence identity with ubiquitin, they are closely related three-dimensionally. For example, SUMO shares only 18% sequence identity, but they contain the same structural fold. This fold is called "ubiquitin fold". FAT10 and UCRP contain two. This compact globular beta-grasp fold is found in ubiquitin, UBLs, and proteins that comprise a ubiquitin-like domain, e.g. the S. cerevisiae spindle pole body duplication protein, Dsk2, and NER protein, Rad23, both contain N-terminal ubiquitin domains.

These related molecules have novel functions and influence diverse biological processes. There is also cross-regulation between the various conjugation pathways, since some proteins can become modified by more than one UBL, and sometimes even at the same lysine residue. For instance, SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates. Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome but rather function in diverse regulatory activities. Attachment of UBLs might, alter substrate conformation, affect the affinity for ligands or other interacting molecules, alter substrate localization, and influence protein stability.

UBLs are structurally similar to ubiquitin and are processed, activated, conjugated, and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin. UBLs are also translated with C-terminal extensions that are processed to expose the invariant C-terminal LRGG. These modifiers have their own specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes that conjugate the UBLs to intracellular targets. These conjugates can be reversed by UBL-specific isopeptidases that have similar mechanisms to that of the deubiquitinating enzymes.[76]

Within some species, the recognition and destruction of sperm mitochondria through a mechanism involving ubiquitin is responsible for sperm mitochondria's disposal after fertilization occurs.[123]

Prokaryotic origins

Ubiquitin is believed to have descended from bacterial proteins similar to ThiS (O32583)[124] or MoaD (P30748).[125] These prokaryotic proteins, despite having little sequence identity (ThiS has 14% identity to ubiquitin), share the same protein fold. These proteins also share sulfur chemistry with ubiquitin. MoaD, which is involved in molybdopterin biosynthesis, interacts with MoeB, which acts like an E1 ubiquitin-activating enzyme for MoaD, strengthening the link between these prokaryotic proteins and the ubiquitin system. A similar system exists for ThiS, with its E1-like enzyme ThiF. It is also believed that the Saccharomyces cerevisiae protein Urm1, a ubiquitin-related modifier, is a "molecular fossil" that connects the evolutionary relation with the prokaryotic ubiquitin-like molecules and ubiquitin.[126]

Archaea have a functionally closer homolog of the ubiquitin modification system, where "sampylation" with SAMPs (small archaeal modifier proteins) is performed. The sampylation system only uses E1 to guide proteins to the proteosome.[127] Proteoarchaeota, which are related to the ancestor of eukaryotes, possess all of the E1, E2, and E3 enzymes plus a regulated Rpn11 system. Unlike SAMP which are more similar to ThiS or MoaD, Proteoarchaeota ubiquitin are most similar to eukaryotic homologs.[128]

Prokaryotic ubiquitin-like protein (Pup) and ubiquitin bacterial (UBact)

Main article: Prokaryotic ubiquitin-like protein

Prokaryotic ubiquitin-like protein (Pup) is a functional analog of ubiquitin which has been found in the gram-positive bacterial phylum Actinomycetota. It serves the same function (targeting proteins for degradations), although the enzymology of ubiquitination and pupylation is different, and the two families share no homology. In contrast to the three-step reaction of ubiquitination, pupylation requires two steps, therefore only two enzymes are involved in pupylation.

In 2017, homologs of Pup were reported in five phyla of gram-negative bacteria, in seven candidate bacterial phyla and in one archaeon[129] The sequences of the Pup homologs are very different from the sequences of Pup in gram-positive bacteria and were termed Ubiquitin bacterial (UBact), although the distinction has yet not been proven to be phylogenetically supported by a separate evolutionary origin and is without experimental evidence.[129]

The finding of the Pup/UBact-proteasome system in both gram-positive and gram-negative bacteria suggests that either the Pup/UBact-proteasome system evolved in bacteria prior to the split into gram positive and negative clades over 3000 million years ago or,[130] that these systems were acquired by different bacterial lineages through horizontal gene transfer(s) from a third, yet unknown, organism. In support of the second possibility, two UBact loci were found in the genome of an uncultured anaerobic methanotrophic Archaeon (ANME-1;locus CBH38808.1 and locus CBH39258.1).

Human proteins containing ubiquitin domain

These include ubiquitin-like proteins.

ANUBL1; BAG1; BAT3/BAG6; C1orf131; DDI1; DDI2; FAU; HERPUD1; HERPUD2; HOPS; IKBKB; ISG15; LOC391257; MIDN; NEDD8; OASL; PARK2; RAD23A; RAD23B; RPS27A; SACS; 8U SF3A1; SUMO1; SUMO2; SUMO3; SUMO4; TMUB1; TMUB2; UBA52; UBB; UBC; UBD; UBFD1; UBL4A; UBL4B; UBL7; UBLCP1; UBQLN1; UBQLN2; UBQLN3; UBQLN4; UBQLNL; UBTD1; UBTD2; UHRF1; UHRF2;

Related proteins

Prediction of ubiquitination

Currently available prediction programs are:

  • UbiPred is a SVM-based prediction server using 31 physicochemical properties for predicting ubiquitination sites.[131]
  • UbPred is a random forest-based predictor of potential ubiquitination sites in proteins. It was trained on a combined set of 266 non-redundant experimentally verified ubiquitination sites available from our experiments and from two large-scale proteomics studies.[132]
  • CKSAAP_UbSite is SVM-based prediction that employs the composition of k-spaced amino acid pairs surrounding a query site (i.e. any lysine in a query sequence) as input, uses the same dataset as UbPred.[133]

Podcast

  • Investigating the ubiquitin proteasome system was the focus of a Dementia Researcher Podcast.[134] The podcast was published on 16 August 2021, hosted by Professor Selina Wray from University College London.

See also

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External links

  • GeneReviews/NCBI/NIH/UW entry on Angelman syndrome
  • OMIM entries on Angelman syndrome
  • "7.340 Ubiquitination: The Proteasome and Human Disease". MIT OpenCourseWare. 2004. Notes from MIT course.
  • Ubiquitin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

August 16, 2023
ubiquitin, confused, with, ubiquinol, small, regulatory, protein, found, most, tissues, eukaryotic, organisms, found, ubiquitously, discovered, 1975, gideon, goldstein, further, characterized, throughout, late, 1970s, 1980s, four, genes, human, genome, code, u. Not to be confused with Ubiquinol Ubiquitin is a small 8 6 kDa regulatory protein found in most tissues of eukaryotic organisms i e it is found ubiquitously It was discovered in 1975 1 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s 2 Four genes in the human genome code for ubiquitin UBB UBC UBA52 and RPS27A 3 Ubiquitin familyA diagram of ubiquitin The seven lysine sidechains are shown in yellow orange IdentifiersSymbolubiquitinPfamPF00240InterProIPR000626PROSITEPDOC00271SCOP21aar SCOPe SUPFAMAvailable protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryThe addition of ubiquitin to a substrate protein is called ubiquitylation or alternatively ubiquitination or ubiquitinylation Ubiquitylation affects proteins in many ways it can mark them for degradation via the proteasome alter their cellular location affect their activity and promote or prevent protein interactions 4 5 6 Ubiquitylation involves three main steps activation conjugation and ligation performed by ubiquitin activating enzymes E1s ubiquitin conjugating enzymes E2s and ubiquitin ligases E3s respectively The result of this sequential cascade is to bind ubiquitin to lysine residues on the protein substrate via an isopeptide bond cysteine residues through a thioester bond serine and threonine residues through an ester bond or the amino group of the protein s N terminus via a peptide bond 7 8 9 The protein modifications can be either a single ubiquitin protein monoubiquitylation or a chain of ubiquitin polyubiquitylation Secondary ubiquitin molecules are always linked to one of the seven lysine residues or the N terminal methionine of the previous ubiquitin molecule These linking residues are represented by a K or M the one letter amino acid notation of lysine and methionine respectively and a number referring to its position in the ubiquitin molecule as in K48 K29 or M1 The first ubiquitin molecule is covalently bound through its C terminal carboxylate group to a particular lysine cysteine serine threonine or N terminus of the target protein Polyubiquitylation occurs when the C terminus of another ubiquitin is linked to one of the seven lysine residues or the first methionine on the previously added ubiquitin molecule creating a chain This process repeats several times leading to the addition of several ubiquitins Only polyubiquitylation on defined lysines mostly on K48 and K29 is related to degradation by the proteasome referred to as the molecular kiss of death while other polyubiquitylations e g on K63 K11 K6 and M1 and monoubiquitylations may regulate processes such as endocytic trafficking inflammation translation and DNA repair 10 The discovery that ubiquitin chains target proteins to the proteasome which degrades and recycles proteins was honored with the Nobel Prize in Chemistry in 2004 8 11 12 Contents 1 Identification 2 The protein 3 Genes 4 Ubiquitylation 4 1 Types 4 1 1 Monoubiquitination 4 1 2 Polyubiquitin chains 4 1 3 Structure 5 Function 5 1 Membrane proteins 5 2 Genomic maintenance 5 3 Transcriptional regulation 6 Deubiquitination 7 Ubiquitin binding domains 8 Disease associations 8 1 Pathogenesis 8 2 Neurodegeneration 8 3 Infection and immunity 8 4 Genetic disorders 8 5 Diagnostic use 8 6 Link to cancer 8 7 Direct loss of function mutation of E3 ubiquitin ligase 8 7 1 Renal cell carcinoma 8 7 2 Breast cancer 8 7 3 Cyclin E 8 8 Increased ubiquitination activity 8 8 1 Cervical cancer 8 8 2 p53 regulation 8 8 3 p27 8 8 4 Efp 8 9 Evasion of ubiquitination 8 9 1 Colorectal cancer 8 9 2 Glioblastoma 8 10 Phosphorylation dependent ubiquitination 8 11 As a drug target 8 11 1 Screening for ubiquitin ligase substrates 8 11 2 Possible therapeutic applications 8 11 3 Challenge 9 Similar proteins 9 1 Prokaryotic origins 10 Prokaryotic ubiquitin like protein Pup and ubiquitin bacterial UBact 11 Human proteins containing ubiquitin domain 12 Related proteins 13 Prediction of ubiquitination 14 Podcast 15 See also 16 References 17 External linksIdentification Edit Surface representation of Ubiquitin Ubiquitin originally ubiquitous immunopoietic polypeptide was first identified in 1975 1 as an 8 6 kDa protein expressed in all eukaryotic cells The basic functions of ubiquitin and the components of the ubiquitylation pathway were elucidated in the early 1980s at the Technion by Aaron Ciechanover Avram Hershko and Irwin Rose for which the Nobel Prize in Chemistry was awarded in 2004 11 The ubiquitylation system was initially characterised as an ATP dependent proteolytic system present in cellular extracts A heat stable polypeptide present in these extracts ATP dependent proteolysis factor 1 APF 1 was found to become covalently attached to the model protein substrate lysozyme in an ATP and Mg2 dependent process 13 Multiple APF 1 molecules were linked to a single substrate molecule by an isopeptide linkage and conjugates were found to be rapidly degraded with the release of free APF 1 Soon after APF 1 protein conjugation was characterised APF 1 was identified as ubiquitin The carboxyl group of the C terminal glycine residue of ubiquitin Gly76 was identified as the moiety conjugated to substrate lysine residues The protein EditUbiquitin properties human which Number of residues 76Molecular mass 8564 8448 DaIsoelectric point pI 6 79Gene names RPS27A UBA80 UBCEP1 UBA52 UBCEP2 UBB UBCSequence single letter MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPD QQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGUbiquitin is a small protein that exists in all eukaryotic cells It performs its myriad functions through conjugation to a large range of target proteins A variety of different modifications can occur The ubiquitin protein itself consists of 76 amino acids and has a molecular mass of about 8 6 kDa Key features include its C terminal tail and the 7 lysine residues It is highly conserved throughout eukaryote evolution human and yeast ubiquitin share 96 sequence identity citation needed Genes EditUbiquitin is encoded in mammals by 4 different genes UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a respectively The UBB and UBC genes code for polyubiquitin precursor proteins 3 Ubiquitylation Edit The ubiquitylation system showing a RING E3 ligase Ubiquitylation also known as ubiquitination or ubiquitinylation is an enzymatic post translational modification in which a ubiquitin protein is attached to a substrate protein This process most commonly binds the last amino acid of ubiquitin glycine 76 to a lysine residue on the substrate An isopeptide bond is formed between the carboxyl group COO of the ubiquitin s glycine and the epsilon amino group e NH 3 of the substrate s lysine 14 Trypsin cleavage of a ubiquitin conjugated substrate leaves a di glycine remnant that is used to identify the site of ubiquitylation 15 16 Ubiquitin can also be bound to other sites in a protein which are electron rich nucleophiles termed non canonical ubiquitylation 9 This was first observed with the amine group of a protein s N terminus being used for ubiquitylation rather than a lysine residue in the protein MyoD 17 and has been observed since in 22 other proteins in multiple species 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 including ubiquitin itself 37 38 There is also increasing evidence for nonlysine residues as ubiquitylation targets using non amine groups such as the sulfhydryl group on cysteine 33 34 39 40 41 42 43 44 45 46 and the hydroxyl group on threonine and serine 33 34 39 45 46 47 48 49 50 The end result of this process is the addition of one ubiquitin molecule monoubiquitylation or a chain of ubiquitin molecules polyubiquitination to the substrate protein 51 Ubiquitination requires three types of enzyme ubiquitin activating enzymes ubiquitin conjugating enzymes and ubiquitin ligases known as E1s E2s and E3s respectively The process consists of three main steps Activation Ubiquitin is activated in a two step reaction by an E1 ubiquitin activating enzyme which is dependent on ATP The initial step involves production of a ubiquitin adenylate intermediate The E1 binds both ATP and ubiquitin and catalyses the acyl adenylation of the C terminus of the ubiquitin molecule The second step transfers ubiquitin to an active site cysteine residue with release of AMP This step results in a thioester linkage between the C terminal carboxyl group of ubiquitin and the E1 cysteine sulfhydryl group 14 52 The human genome contains two genes that produce enzymes capable of activating ubiquitin UBA1 and UBA6 53 Conjugation E2 ubiquitin conjugating enzymes catalyse the transfer of ubiquitin from E1 to the active site cysteine of the E2 via a trans thio esterification reaction In order to perform this reaction the E2 binds to both activated ubiquitin and the E1 enzyme Humans possess 35 different E2 enzymes whereas other eukaryotic organisms have between 16 and 35 They are characterised by their highly conserved structure known as the ubiquitin conjugating catalytic UBC fold 54 Glycine and lysine linked by an isopeptide bond The isopeptide bond is highlighted yellow Ligation E3 ubiquitin ligases catalyse the final step of the ubiquitination cascade Most commonly they create an isopeptide bond between a lysine of the target protein and the C terminal glycine of ubiquitin In general this step requires the activity of one of the hundreds of E3s E3 enzymes function as the substrate recognition modules of the system and are capable of interaction with both E2 and substrate Some E3 enzymes also activate the E2 enzymes E3 enzymes possess one of two domains the homologous to the E6 AP carboxyl terminus HECT domain and the really interesting new gene RING domain or the closely related U box domain HECT domain E3s transiently bind ubiquitin in this process an obligate thioester intermediate is formed with the active site cysteine of the E3 whereas RING domain E3s catalyse the direct transfer from the E2 enzyme to the substrate 55 The anaphase promoting complex APC and the SCF complex for Skp1 Cullin F box protein complex are two examples of multi subunit E3s involved in recognition and ubiquitination of specific target proteins for degradation by the proteasome 56 In the ubiquitination cascade E1 can bind with many E2s which can bind with hundreds of E3s in a hierarchical way Having levels within the cascade allows tight regulation of the ubiquitination machinery 7 Other ubiquitin like proteins UBLs are also modified via the E1 E2 E3 cascade although variations in these systems do exist 57 E4 enzymes or ubiquitin chain elongation factors are capable of adding pre formed polyubiquitin chains to substrate proteins 58 For example multiple monoubiquitylation of the tumor suppressor p53 by Mdm2 59 can be followed by addition of a polyubiquitin chain using p300 and CBP 60 61 Types Edit See also Ubiquitin ligase Mono and poly ubiquitylation Ubiquitination affects cellular process by regulating the degradation of proteins via the proteasome and lysosome coordinating the cellular localization of proteins activating and inactivating proteins and modulating protein protein interactions 4 5 6 These effects are mediated by different types of substrate ubiquitination for example the addition of a single ubiquitin molecule monoubiquitination or different types of ubiquitin chains polyubiquitination 62 Monoubiquitination Edit Monoubiquitination is the addition of one ubiquitin molecule to one substrate protein residue Multi monoubiquitination is the addition of one ubiquitin molecule to multiple substrate residues The monoubiquitination of a protein can have different effects to the polyubiquitination of the same protein The addition of a single ubiquitin molecule is thought to be required prior to the formation of polyubiquitin chains 62 Monoubiquitination affects cellular processes such as membrane trafficking endocytosis and viral budding 10 63 Polyubiquitin chains Edit Diagram of lysine 48 linked diubiquitin The linkage between the two ubiquitin chains is shown in orange Diagram of lysine 63 linked diubiquitin The linkage between the two ubiquitin chains is shown in orange Polyubiquitination is the formation of a ubiquitin chain on a single lysine residue on the substrate protein Following addition of a single ubiquitin moiety to a protein substrate further ubiquitin molecules can be added to the first yielding a polyubiquitin chain 62 These chains are made by linking the glycine residue of a ubiquitin molecule to a lysine of ubiquitin bound to a substrate Ubiquitin has seven lysine residues and an N terminus that serves as points of ubiquitination they are K6 K11 K27 K29 K33 K48 K63 and M1 respectively 8 Lysine 48 linked chains were the first identified and are the best characterised type of ubiquitin chain K63 chains have also been well characterised whereas the function of other lysine chains mixed chains branched chains M1 linked linear chains and heterologous chains mixtures of ubiquitin and other ubiquitin like proteins remains more unclear 16 38 62 63 64 Lysine 48 linked polyubiquitin chains target proteins for destruction by a process known as proteolysis Multi ubiquitin chains at least four ubiquitin molecules long must be attached to a lysine residue on the condemned protein in order for it to be recognised by the 26S proteasome 65 This is a barrel shape structure comprising a central proteolytic core made of four ring structures flanked by two cylinders that selectively allow entry of ubiquitinated proteins Once inside the proteins are rapidly degraded into small peptides usually 3 25 amino acid residues in length Ubiquitin molecules are cleaved off the protein immediately prior to destruction and are recycled for further use 66 Although the majority of protein substrates are ubiquitinated there are examples of non ubiquitinated proteins targeted to the proteasome 67 The polyubiquitin chains are recognised by a subunit of the proteasome S5a Rpn10 This is achieved by a ubiquitin interacting motif UIM found in a hydrophobic patch in the C terminal region of the S5a Rpn10 unit 4 Lysine 63 linked chains are not associated with proteasomal degradation of the substrate protein Instead they allow the coordination of other processes such as endocytic trafficking inflammation translation and DNA repair 10 In cells lysine 63 linked chains are bound by the ESCRT 0 complex which prevents their binding to the proteasome This complex contains two proteins Hrs and STAM1 that contain a UIM which allows it to bind to lysine 63 linked chains 68 69 Methionine 1 linked or linear polyubiquitin chains are another type of non degradative ubiquitin chains In this case ubiquitin is linked in a head to tail manner meaning that the C terminus of the last ubiquitin molecule binds directly to the N terminus of the next one Although initially believed to target proteins for proteasomal degradation 70 linear ubiquitin later proved to be indispensable for NF kB signaling 71 Currently there is only one known E3 ubiquitin ligase generating M1 linked polyubiquitin chains linear ubiquitin chain assembly complex LUBAC 38 72 Less is understood about atypical non lysine 48 linked ubiquitin chains but research is starting to suggest roles for these chains 63 There is evidence to suggest that atypical chains linked by lysine 6 11 27 29 and methionine 1 can induce proteasomal degradation 67 73 Branched ubiquitin chains containing multiple linkage types can be formed 74 The function of these chains is unknown 8 Structure Edit Differently linked chains have specific effects on the protein to which they are attached caused by differences in the conformations of the protein chains K29 K33 75 K63 and M1 linked chains have a fairly linear conformation they are known as open conformation chains K6 K11 and K48 linked chains form closed conformations The ubiquitin molecules in open conformation chains do not interact with each other except for the covalent isopeptide bonds linking them together In contrast the closed conformation chains have interfaces with interacting residues Altering the chain conformations exposes and conceals different parts of the ubiquitin protein and the different linkages are recognized by proteins that are specific for the unique topologies that are intrinsic to the linkage Proteins can specifically bind to ubiquitin via ubiquitin binding domains UBDs The distances between individual ubiquitin units in chains differ between lysine 63 and 48 linked chains The UBDs exploit this by having small spacers between ubiquitin interacting motifs that bind lysine 48 linked chains compact ubiquitin chains and larger spacers for lysine 63 linked chains The machinery involved in recognising polyubiquitin chains can also differentiate between K63 linked chains and M1 linked chains demonstrated by the fact that the latter can induce proteasomal degradation of the substrate 8 10 73 Function EditThe ubiquitination system functions in a wide variety of cellular processes including 76 Antigen processing Apoptosis Biogenesis of organelles Cell cycle and division DNA transcription and repair Differentiation and development Immune response and inflammation Neural and muscular degeneration Maintenance of pluripotency 77 Morphogenesis of neural networks Modulation of cell surface receptors ion channels and the secretory pathway Response to stress and extracellular modulators Ribosome biogenesis Viral infectionMembrane proteins Edit Multi monoubiquitination can mark transmembrane proteins for example receptors for removal from membranes internalisation and fulfil several signalling roles within the cell When cell surface transmembrane molecules are tagged with ubiquitin the subcellular localization of the protein is altered often targeting the protein for destruction in lysosomes This serves as a negative feedback mechanism because often the stimulation of receptors by ligands increases their rate of ubiquitination and internalisation Like monoubiquitination lysine 63 linked polyubiquitin chains also has a role in the trafficking some membrane proteins 10 62 65 78 Genomic maintenance Edit Proliferating cell nuclear antigen PCNA is a protein involved in DNA synthesis Under normal physiological conditions PCNA is sumoylated a similar post translational modification to ubiquitination When DNA is damaged by ultra violet radiation or chemicals the SUMO molecule that is attached to a lysine residue is replaced by ubiquitin Monoubiquitinated PCNA recruits polymerases that can carry out DNA synthesis with damaged DNA but this is very error prone possibly resulting in the synthesis of mutated DNA Lysine 63 linked polyubiquitination of PCNA allows it to perform a less error prone mutation bypass known by the template switching pathway 6 79 80 Ubiquitination of histone H2AX is involved in DNA damage recognition of DNA double strand breaks Lysine 63 linked polyubiquitin chains are formed on H2AX histone by the E2 E3 ligase pair Ubc13 Mms2 RNF168 81 82 This K63 chain appears to recruit RAP80 which contains a UIM and RAP80 then helps localize BRCA1 This pathway will eventually recruit the necessary proteins for homologous recombination repair 83 Transcriptional regulation Edit Histones can be ubiquitinated and this is usually in the form of monoubiquitination although polyubiquitinated forms do occur Histone ubiquitination alters chromatin structure and allows the access of enzymes involved in transcription Ubiquitin on histones also acts as a binding site for proteins that either activate or inhibit transcription and also can induce further post translational modifications of the protein These effects can all modulate the transcription of genes 84 85 Deubiquitination EditDeubiquitinating enzymes DUBs oppose the role of ubiquination by removing ubiquitin from substrate proteins They are cysteine proteases that cleave the amide bond between the two proteins They are highly specific as are the E3 ligases that attach the ubiquitin with only a few substrates per enzyme They can cleave both isopeptide between ubiquitin and lysine and peptide bonds between ubiquitin and the N terminus In addition to removing ubiquitin from substrate proteins DUBs have many other roles within the cell Ubiquitin is either expressed as multiple copies joined in a chain polyubiquitin or attached to ribosomal subunits DUBs cleave these proteins to produce active ubiquitin They also recycle ubiquitin that has been bound to small nucleophilic molecules during the ubiquitination process Monoubiquitin is formed by DUBs that cleave ubiquitin from free polyubiquitin chains that have been previously removed from proteins 86 87 Ubiquitin binding domains EditTable of characterized Ubiquitin binding domains 88 Domain Number of proteins in proteome Length amino acids Ubiquitin binding AffinityCUE S cerevisiae 7 H sapiens 21 42 43 2 160 mMGATII S cerevisiae 2 H sapiens 14 135 180 mMGLUE S cerevisiae H sapiens 135 460 mMNZF S cerevisiae 1 H sapiens 25 35 100 400 mMPAZ S cerevisiae 5 H sapiens 16 58 Not knownUBA S cerevisiae 10 H sapiens 98 45 55 0 03 500 mMUEV S cerevisiae 2 H sapiens 145 100 500 mMUIM S cerevisiae 8 H sapiens 71 20 100 400 mMVHS S cerevisiae 4 H sapiens 28 150 Not knownUbiquitin binding domains UBDs are modular protein domains that non covalently bind to ubiquitin these motifs control various cellular events Detailed molecular structures are known for a number of UBDs binding specificity determines their mechanism of action and regulation and how it regulates cellular proteins and processes 88 89 Disease associations EditPathogenesis Edit The ubiquitin pathway has been implicated in the pathogenesis of a wide range of diseases and disorders including 90 Neurodegeneration Infection and immunity Genetic disorders CancerNeurodegeneration Edit Ubiquitin is implicated in neurodegenerative diseases associated with proteostasis dysfunction including Alzheimer s disease motor neuron disease 91 Huntington s disease and Parkinson s disease 90 Transcript variants encoding different isoforms of ubiquilin 1 are found in lesions associated with Alzheimer s and Parkinson s disease 92 Higher levels of ubiquilin in the brain have been shown to decrease malformation of amyloid precursor protein APP which plays a key role in triggering Alzheimer s disease 93 Conversely lower levels of ubiquilin 1 in the brain have been associated with increased malformation of APP 93 A frameshift mutation in ubiquitin B can result in a truncated peptide missing the C terminal glycine This abnormal peptide known as UBB 1 has been shown to accumulate selectively in Alzheimer s disease and other tauopathies Infection and immunity Edit Ubiquitin and ubiquitin like molecules extensively regulate immune signal transduction pathways at virtually all stages including steady state repression activation during infection and attenuation upon clearance Without this regulation immune activation against pathogens may be defective resulting in chronic disease or death Alternatively the immune system may become hyperactivated and organs and tissues may be subjected to autoimmune damage On the other hand viruses must block or redirect host cell processes including immunity to effectively replicate yet many viruses relevant to disease have informationally limited genomes Because of its very large number of roles in the cell manipulating the ubiquitin system represents an efficient way for such viruses to block subvert or redirect critical host cell processes to support their own replication 94 The retinoic acid inducible gene I RIG I protein is a primary immune system sensor for viral and other invasive RNA in human cells 95 The RIG I like receptor RLR immune signaling pathway is one of the most extensively studied in terms of the role of ubiquitin in immune regulation 96 Genetic disorders Edit Angelman syndrome is caused by a disruption of UBE3A which encodes a ubiquitin ligase E3 enzyme termed E6 AP Von Hippel Lindau syndrome involves disruption of a ubiquitin E3 ligase termed the VHL tumor suppressor or VHL gene Fanconi anemia Eight of the thirteen identified genes whose disruption can cause this disease encode proteins that form a large ubiquitin ligase E3 complex 3 M syndrome is an autosomal recessive growth retardation disorder associated with mutations of the Cullin7 E3 ubiquitin ligase 97 Diagnostic use Edit Immunohistochemistry using antibodies to ubiquitin can identify abnormal accumulations of this protein inside cells indicating a disease process These protein accumulations are referred to as inclusion bodies which is a general term for any microscopically visible collection of abnormal material in a cell Examples include Neurofibrillary tangles in Alzheimer s disease Lewy body in Parkinson s disease Pick bodies in Pick s disease Inclusions in motor neuron disease and Huntington s disease Mallory bodies in alcoholic liver disease Rosenthal fibers in astrocytesLink to cancer Edit Post translational modification of proteins is a generally used mechanism in eukaryotic cell signaling 98 Ubiquitination or ubiquitin conjugation to proteins is a crucial process for cell cycle progression and cell proliferation and development Although ubiquitination usually serves as a signal for protein degradation through the 26S proteasome it could also serve for other fundamental cellular processes 98 e g in endocytosis 99 enzymatic activation 100 and DNA repair 101 Moreover since ubiquitination functions to tightly regulate the cellular level of cyclins its misregulation is expected to have severe impacts First evidence of the importance of the ubiquitin proteasome pathway in oncogenic processes was observed due to the high antitumor activity of proteasome inhibitors 102 103 104 Various studies have shown that defects or alterations in ubiquitination processes are commonly associated with or present in human carcinoma 105 106 107 108 109 110 111 112 Malignancies could be developed through loss of function mutation directly at the tumor suppressor gene increased activity of ubiquitination and or indirect attenuation of ubiquitination due to mutation in related proteins 113 Direct loss of function mutation of E3 ubiquitin ligase Edit Renal cell carcinoma Edit The VHL Von Hippel Lindau gene encodes a component of an E3 ubiquitin ligase VHL complex targets a member of the hypoxia inducible transcription factor family HIF for degradation by interacting with the oxygen dependent destruction domain under normoxic conditions HIF activates downstream targets such as the vascular endothelial growth factor VEGF promoting angiogenesis Mutations in VHL prevent degradation of HIF and thus lead to the formation of hypervascular lesions and renal tumors 105 113 Breast cancer Edit The BRCA1 gene is another tumor suppressor gene in humans which encodes the BRCA1 protein that is involved in response to DNA damage The protein contains a RING motif with E3 Ubiquitin Ligase activity BRCA1 could form dimer with other molecules such as BARD1 and BAP1 for its ubiquitination activity Mutations that affect the ligase function are often found and associated with various cancers 109 113 Cyclin E Edit As processes in cell cycle progression are the most fundamental processes for cellular growth and differentiation and are the most common to be altered in human carcinomas it is expected for cell cycle regulatory proteins to be under tight regulation The level of cyclins as the name suggests is high only at certain a time point during the cell cycle This is achieved by continuous control of cyclins or CDKs levels through ubiquitination and degradation When cyclin E is partnered with CDK2 and gets phosphorylated an SCF associated F box protein Fbw7 recognizes the complex and thus targets it for degradation Mutations in Fbw7 have been found in more than 30 of human tumors characterizing it as a tumor suppressor protein 112 Increased ubiquitination activity Edit Cervical cancer Edit Oncogenic types of the human papillomavirus HPV are known to hijack cellular ubiquitin proteasome pathway for viral infection and replication The E6 proteins of HPV will bind to the N terminus of the cellular E6 AP E3 ubiquitin ligase redirecting the complex to bind p53 a well known tumor suppressor gene whose inactivation is found in many types of cancer 107 Thus p53 undergoes ubiquitination and proteasome mediated degradation Meanwhile E7 another one of the early expressed HPV genes will bind to Rb also a tumor suppressor gene mediating its degradation 113 The loss of p53 and Rb in cells allows limitless cell proliferation to occur p53 regulation Edit Gene amplification often occur in various tumor cases including of MDM2 a gene encodes for a RING E3 Ubiquitin ligase responsible for downregulation of p53 activity MDM2 targets p53 for ubiquitination and proteasomal degradation thus keeping its level appropriate for normal cell condition Overexpression of MDM2 causes loss of p53 activity and therefore allowing cells to have a limitless replicative potential 108 113 p27 Edit Another gene that is a target of gene amplification is SKP2 SKP2 is an F box protein with a role in substrate recognition for ubiquitination and degradation SKP2 targets p27Kip 1 an inhibitor of cyclin dependent kinases CDKs CDKs2 4 partner with the cyclins E D respectively forming a family of cell cycle regulators which control cell cycle progression through the G1 phase Low level of p27Kip 1 protein is often found in various cancers and is due to overactivation of ubiquitin mediated proteolysis through overexpression of SKP2 110 113 Efp Edit Efp or estrogen inducible RING finger protein is an E3 ubiquitin ligase whose overexpression has been shown to be the major cause of estrogen independent breast cancer 104 114 Efp s substrate is 14 3 3 protein which negatively regulates cell cycle Evasion of ubiquitination Edit Colorectal cancer Edit The gene associated with colorectal cancer is the adenomatous polyposis coli APC which is a classic tumor suppressor gene APC gene product targets beta catenin for degradation via ubiquitination at the N terminus thus regulating its cellular level Most colorectal cancer cases are found with mutations in the APC gene However in cases where APC gene is not mutated mutations are found in the N terminus of beta catenin which renders it ubiquitination free and thus increased activity 106 113 Glioblastoma Edit As the most aggressive cancer originated in the brain mutations found in patients with glioblastoma are related to the deletion of a part of the extracellular domain of the epidermal growth factor receptor EGFR This deletion causes CBL E3 ligase unable to bind to the receptor for its recycling and degradation via a ubiquitin lysosomal pathway Thus EGFR is constitutively active in the cell membrane and activates its downstream effectors that are involved in cell proliferation and migration 111 Phosphorylation dependent ubiquitination Edit The interplay between ubiquitination and phosphorylation has been an ongoing research interest since phosphorylation often serves as a marker where ubiquitination leads to degradation 98 Moreover ubiquitination can also act to turn on off the kinase activity of a protein 115 The critical role of phosphorylation is largely underscored in the activation and removal of autoinhibition in the Cbl protein 116 Cbl is an E3 ubiquitin ligase with a RING finger domain that interacts with its tyrosine kinase binding TKB domain preventing interaction of the RING domain with an E2 ubiquitin conjugating enzyme This intramolecular interaction is an autoinhibition regulation that prevents its role as a negative regulator of various growth factors and tyrosine kinase signaling and T cell activation 116 Phosphorylation of Y363 relieves the autoinhibition and enhances binding to E2 116 Mutations that render the Cbl protein dysfunctional due to the loss of its ligase tumor suppressor function and maintenance of its positive signaling oncogenic function have been shown to cause the development of cancer 117 118 As a drug target Edit Screening for ubiquitin ligase substrates Edit Deregulation of E3 substrate interactions is a key cause of many human disorders therefore identifying E3 ligase substrates is crucial In 2008 Global Protein Stability GPS Profiling was developed to discover E3 ubiquitin ligase substrates 119 This high throughput system made use of reporter proteins fused with thousands of potential substrates independently By inhibition of the ligase activity through the making of Cul1 dominant negative thus renders ubiquitination not to occur increased reporter activity shows that the identified substrates are being accumulated This approach added a large number of new substrates to the list of E3 ligase substrates Possible therapeutic applications Edit Blocking of specific substrate recognition by the E3 ligases e g bortezomib 114 Challenge Edit Finding a specific molecule that selectively inhibits the activity of a certain E3 ligase and or the protein protein interactions implicated in the disease remains as one of the important and expanding research area Moreover as ubiquitination is a multi step process with various players and intermediate forms consideration of the much complex interactions between components needs to be taken heavily into account while designing the small molecule inhibitors 104 Similar proteins EditMain article Ubiquitin like protein Ubiquitin is the most understood post translation modifier however several family of ubiquitin like proteins UBLs are found can modify cellular targets in a parallel but distinct route Known UBLs include small ubiquitin like modifier SUMO ubiquitin cross reactive protein UCRP also known as interferon stimulated gene 15 ISG15 ubiquitin related modifier 1 URM1 neuronal precursor cell expressed developmentally downregulated protein 8 NEDD8 also called Rub1 in S cerevisiae human leukocyte antigen F associated FAT10 autophagy 8 ATG8 and 12 ATG12 Few ubiquitin like protein FUB1 MUB membrane anchored UBL 120 ubiquitin fold modifier 1 UFM1 and ubiquitin like protein 5 UBL5 which is but known as homologous to ubiquitin 1 Hub1 in S pombe 121 122 Although these proteins share only modest primary sequence identity with ubiquitin they are closely related three dimensionally For example SUMO shares only 18 sequence identity but they contain the same structural fold This fold is called ubiquitin fold FAT10 and UCRP contain two This compact globular beta grasp fold is found in ubiquitin UBLs and proteins that comprise a ubiquitin like domain e g the S cerevisiae spindle pole body duplication protein Dsk2 and NER protein Rad23 both contain N terminal ubiquitin domains These related molecules have novel functions and influence diverse biological processes There is also cross regulation between the various conjugation pathways since some proteins can become modified by more than one UBL and sometimes even at the same lysine residue For instance SUMO modification often acts antagonistically to that of ubiquitination and serves to stabilize protein substrates Proteins conjugated to UBLs are typically not targeted for degradation by the proteasome but rather function in diverse regulatory activities Attachment of UBLs might alter substrate conformation affect the affinity for ligands or other interacting molecules alter substrate localization and influence protein stability UBLs are structurally similar to ubiquitin and are processed activated conjugated and released from conjugates by enzymatic steps that are similar to the corresponding mechanisms for ubiquitin UBLs are also translated with C terminal extensions that are processed to expose the invariant C terminal LRGG These modifiers have their own specific E1 activating E2 conjugating and E3 ligating enzymes that conjugate the UBLs to intracellular targets These conjugates can be reversed by UBL specific isopeptidases that have similar mechanisms to that of the deubiquitinating enzymes 76 Within some species the recognition and destruction of sperm mitochondria through a mechanism involving ubiquitin is responsible for sperm mitochondria s disposal after fertilization occurs 123 Prokaryotic origins Edit Ubiquitin is believed to have descended from bacterial proteins similar to ThiS O32583 124 or MoaD P30748 125 These prokaryotic proteins despite having little sequence identity ThiS has 14 identity to ubiquitin share the same protein fold These proteins also share sulfur chemistry with ubiquitin MoaD which is involved in molybdopterin biosynthesis interacts with MoeB which acts like an E1 ubiquitin activating enzyme for MoaD strengthening the link between these prokaryotic proteins and the ubiquitin system A similar system exists for ThiS with its E1 like enzyme ThiF It is also believed that the Saccharomyces cerevisiae protein Urm1 a ubiquitin related modifier is a molecular fossil that connects the evolutionary relation with the prokaryotic ubiquitin like molecules and ubiquitin 126 Archaea have a functionally closer homolog of the ubiquitin modification system where sampylation with SAMPs small archaeal modifier proteins is performed The sampylation system only uses E1 to guide proteins to the proteosome 127 Proteoarchaeota which are related to the ancestor of eukaryotes possess all of the E1 E2 and E3 enzymes plus a regulated Rpn11 system Unlike SAMP which are more similar to ThiS or MoaD Proteoarchaeota ubiquitin are most similar to eukaryotic homologs 128 Prokaryotic ubiquitin like protein Pup and ubiquitin bacterial UBact EditMain article Prokaryotic ubiquitin like protein Prokaryotic ubiquitin like protein Pup is a functional analog of ubiquitin which has been found in the gram positive bacterial phylum Actinomycetota It serves the same function targeting proteins for degradations although the enzymology of ubiquitination and pupylation is different and the two families share no homology In contrast to the three step reaction of ubiquitination pupylation requires two steps therefore only two enzymes are involved in pupylation In 2017 homologs of Pup were reported in five phyla of gram negative bacteria in seven candidate bacterial phyla and in one archaeon 129 The sequences of the Pup homologs are very different from the sequences of Pup in gram positive bacteria and were termed Ubiquitin bacterial UBact although the distinction has yet not been proven to be phylogenetically supported by a separate evolutionary origin and is without experimental evidence 129 The finding of the Pup UBact proteasome system in both gram positive and gram negative bacteria suggests that either the Pup UBact proteasome system evolved in bacteria prior to the split into gram positive and negative clades over 3000 million years ago or 130 that these systems were acquired by different bacterial lineages through horizontal gene transfer s from a third yet unknown organism In support of the second possibility two UBact loci were found in the genome of an uncultured anaerobic methanotrophic Archaeon ANME 1 locus CBH38808 1 and locus CBH39258 1 Human proteins containing ubiquitin domain EditThese include ubiquitin like proteins ANUBL1 BAG1 BAT3 BAG6 C1orf131 DDI1 DDI2 FAU HERPUD1 HERPUD2 HOPS IKBKB ISG15 LOC391257 MIDN NEDD8 OASL PARK2 RAD23A RAD23B RPS27A SACS 8U SF3A1 SUMO1 SUMO2 SUMO3 SUMO4 TMUB1 TMUB2 UBA52 UBB UBC UBD UBFD1 UBL4A UBL4B UBL7 UBLCP1 UBQLN1 UBQLN2 UBQLN3 UBQLN4 UBQLNL UBTD1 UBTD2 UHRF1 UHRF2 Related proteins EditUbiquitin associated protein domainPrediction of ubiquitination EditCurrently available prediction programs are UbiPred is a SVM based prediction server using 31 physicochemical properties for predicting ubiquitination sites 131 UbPred is a random forest based predictor of potential ubiquitination sites in proteins It was trained on a combined set of 266 non redundant experimentally verified ubiquitination sites available from our experiments and from two large scale proteomics studies 132 CKSAAP UbSite is SVM based prediction that employs the composition of k spaced amino acid pairs surrounding a query site i e any lysine in a query sequence as input uses the same dataset as UbPred 133 Podcast EditInvestigating the ubiquitin proteasome system was the focus of a Dementia Researcher Podcast 134 The podcast was published on 16 August 2021 hosted by Professor Selina Wray from University College London See also EditAutophagy Autophagin Endoplasmic reticulum associated protein degradation JUNQ and IPOD Prokaryotic ubiquitin like protein SUMO enzymesReferences Edit a b Goldstein G Scheid M Hammerling U Schlesinger DH Niall HD Boyse EA January 1975 Isolation of a polypeptide that has lymphocyte differentiating properties and is probably represented 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Fraternali F ed Prediction of ubiquitination sites by using the composition of k spaced amino acid pairs PLOS ONE 6 7 e22930 Bibcode 2011PLoSO 622930C doi 10 1371 journal pone 0022930 PMC 3146527 PMID 21829559 Stream episode Investigating the ubiquitin proteasome system by Dementia Researcher podcast Listen online for free on SoundCloud External links EditGeneReviews NCBI NIH UW entry on Angelman syndrome OMIM entries on Angelman syndrome UniProt entry for ubiquitin 7 340 Ubiquitination The Proteasome and Human Disease MIT OpenCourseWare 2004 Notes from MIT course Ubiquitin at the U S National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Ubiquitin amp oldid 1166008303 Ubiquitylation, wikipedia, wiki, book, books, library,

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