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Ankyrin repeat

December 15, 2023

The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and Drosophila Notch. Domains consisting of ankyrin tandem repeats mediate protein–protein interactions and are among the most common structural motifs in known proteins. They appear in bacterial, archaeal, and eukaryotic proteins, but are far more common in eukaryotes. Ankyrin repeat proteins, though absent in most viruses, are common among poxviruses. Most proteins that contain the motif have four to six repeats, although its namesake ankyrin contains 24, and the largest known number of repeats is 34, predicted in a protein expressed by Giardia lamblia.[2]

Ankyrin repeat domain
Ribbon diagram of a fragment of the membrane-binding domain of ankyrin R.[1]
Identifiers
SymbolAnk
PfamPF00023
InterProIPR002110
SMARTSM00248
PROSITEPDOC50088
SCOP21awc / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1a5e​, 1ap7​, 1awc​, 1bd8​, 1bi7​, 1bi8​, 1blx​, 1bu9​, 1d9s​, 1dc2​, 1dcq​, 1g3n​, 1ihb​, 1ikn​, 1ixv​, 1k1a​, 1k1b​, 1k3z​, 1mx2​, 1mx4​, 1mx6​, 1myo​, 1n11​, 1nfi​, 1ot8​, 1oy3​, 1qym​, 1s70​, 1svc​, 1sw6​, 1tr4​, 1uoh​, 1wdy​, 1wfu​, 1wg0​, 1ycs​, 1yyh​, 1zlm​, 2a5e​, 2f8x​, 2f8y​, 2he0​, 2myo​

Ankyrin repeats typically fold together to form a single, linear solenoid structure called ankyrin repeat domains. These domains are one of the most common protein–protein interaction platforms in nature. They occur in a large number of functionally diverse proteins, mainly from eukaryotes. The few known examples from prokaryotes and viruses may be the result of horizontal gene transfers.[3] The repeat has been found in proteins of diverse function such as transcriptional initiators, cell cycle regulators, cytoskeletal, ion transporters, and signal transducers. The ankyrin fold appears to be defined by its structure rather than its function, since there is no specific sequence or structure that is universally recognised by it.

Considering the atomic structures of individual ankyrin repeats, the loop is often a type 1 beta bulge loop, while both alpha-helices commonly have a Schellman loop at their N-terminus.

Role in protein folding edit

The ankyrin-repeat sequence motif has been studied using multiple sequence alignment to determine conserved amino acid residues critical for folding and stability. The residues on the wide lateral surface of ankyrin repeat structures are variable, often hydrophobic, and involved mainly in mediating protein–protein interactions. An artificial protein design based on a consensus sequence derived from sequence alignment has been synthesized and found to fold stably, representing the first designed protein with multiple repeats.[4] More extensive design strategies have used combinatorial sequences to "evolve" ankyrin-repeats that recognize particular protein targets, a technique that has been presented as an alternative to antibody design for applications requiring high-affinity binding.[5] A structure-based study involving a range of ankyrin proteins of known structures, shows that consensus-based ankyrin proteins are very stable since they maximize the energetic gap between the folding and unfolding structures, encoding a densely connected network of favourable interactions among conserved sequence motifs, like the TPLX motif.[6] The same study shows that insertions in the canonical framework of ankyrin repeats are enriched in conflictive interactions, that are related to function. The same applies to interactions surrounding deletion hotspots. These might be related to complex folding/unfolding transitions that are important to the partner recognition and interaction.

Ankyrin-repeat proteins present an unusual problem in the study of protein folding, which has largely focused on globular proteins that form well-defined tertiary structure stabilized by long-range, nonlocal residue-residue contacts. Ankyrin repeats, by contrast, contain very few such contacts (that is, they have a low contact order). Most studies have found that ankyrin repeats fold in a two-state folding mechanism, suggesting a high degree of folding cooperativity despite the local inter-residue contacts and the evident need for successful folding with varying numbers of repeats. Some evidence, based on synthesis of truncated versions of natural repeat proteins,[7] and on the examination of phi values,[8] suggests that the C-terminus forms the folding nucleation site.

Clinical significance edit

Ankyrin-repeat proteins have been associated with a number of human diseases. These proteins include the cell cycle inhibitor p16, which is associated with cancer, and the Notch protein (a key component of cell signalling pathways) which can cause the neurological disorder CADASIL when the repeat domain is disrupted by mutations.[2]

A specialized family of ankyrin proteins known as muscle ankyrin repeat proteins (MARPs) are involved with the repair and regeneration of muscle tissue following damage due to injury and stress.[9]

A natural variation between glutamine and lysine at position 703 in the 11th ankyrin repeat of ANKK1, known as the TaqI A1 allele,[10] has been credited with encouraging addictive behaviours such as obesity, alcoholism, nicotine dependency and the Eros love style[citation needed] while discouraging juvenile delinquency and neuroticism-anxiety.[11][failed verification] The variation may affect the specificity of protein interactions made by the ANKK1 protein kinase through this repeat[citation needed].

Human proteins containing this repeat edit

ABTB1; ABTB2; ACBD6; ACTBL1; ANK1; ANK2; ANK3; ANKAR; ANKDD1A; ANKEF1; ANKFY1; ANKHD1; ANKIB1; ANKK1; ANKMY1; ANKMY2; ANKRA2; ANKRD1; ANKRD10; ANKRD11; ANKRD12; ANKRD13; ANKRD13A; ANKRD13B; ANKRD13C; ANKRD13D; ANKRD15; ANKRD16; ANKRD17; ANKRD18A; ANKRD18B; ANKRD19; ANKRD2; ANKRD20A1; ANKRD20A2; ANKRD20A3; ANKRD20A4; ANKRD21; ANKRD22; ANKRD23; ANKRD24; ANKRD25; ANKRD26; ANKRD27; ANKRD28; ANKRD30A; ANKRD30B; ANKRD30BL; ANKRD32; ANKRD33; ANKRD35; ANKRD36; ANKRD36B; ANKRD37; ANKRD38; ANKRD39; ANKRD40; ANKRD41; ANKRD42; ANKRD43; ANKRD44; ANKRD45; ANKRD46; ANKRD47; ANKRD49 [uk]; ANKRD50; ANKRD52; ANKRD53; ANKRD54; ANKRD55; ANKRD56; ANKRD57; ANKRD58; ANKRD60; ANKRD6; ANKRD7; ANKRD9; ANKS1A; ANKS3; ANKS4B; ANKS6; ANKZF1; ASB1; ASB10; ASB11; ASB12; ASB13; ASB14; ASB15; ASB16; ASB2; ASB3; ASB4; ASB5; ASB6; ASB7; ASB8; ASB9; ASZ1; BARD1; BAT4; BAT8; BCL3; BCOR; BCORL1; BTBD11; CAMTA1; CAMTA2; CASKIN1; CASKIN2; CCM1; CDKN2A; CDKN2B; CDKN2C; CDKN2D; CENTB1; CENTB2; CENTB5; CENTG1; CENTG2; CENTG3; CLIP3; CLIP4; CLPB; CTGLF1; CTGLF2; CTGLF3; CTGLF4; CTGLF5; CTTNBP2; DAPK1; DDEF1; DDEF2; DDEFL1; DGKI; DGKZ; DP58; DYSFIP1; DZANK; EHMT1; EHMT2; ESPN; FANK1; FEM1A; FEM1B; GABPB2; GIT1; GIT2; GLS; GLS2; HACE1; HECTD1; IBTK; ILK; INVS; KIDINS220; KRIT1; LRRK1; MAIL; MIB1; MIB2; MPHOSPH8; MTPN; MYO16; NFKB1; NFKB2; NFKBIA; NFKBIB; NFKBIE; NFKBIL1; NFKBIL2; NOTCH1; NOTCH2; NOTCH3; NOTCH4; NRARP; NUDT12; OSBPL1A; OSTF1; PLA2G6; POTE14; POTE15; POTE8; PPP1R12A; PPP1R12B; PPP1R12C; PPP1R13B; PPP1R13L; PPP1R16A; PPP1R16B; PSMD10; RAI14; RFXANK; RIPK4; RNASEL; SHANK1; SHANK2; SHANK3; SNCAIP; TA-NFKBH; TEX14; TNKS; TNKS2; TNNI3K; TP53BP2; TRP7; TRPA1; TRPC3; TRPC4; TRPC5; TRPC6; TRPC7; TRPV1; TRPV2; TRPV3; TRPV4; TRPV5; TRPV6; UACA; USH1G; ZDHHC13; ZDHHC17;

See also edit

  • DARPin (designed ankyrin repeat protein), an engineered antibody mimetic based on the structure of ankyrin repeats

References edit

  1. ^ PDB: 1N11​; Michaely P, Tomchick DR, Machius M, Anderson RG (December 2002). "Crystal structure of a 12 ANK repeat stack from human ANK1". EMBO J. 21 (23): 6387–96. doi:10.1093/emboj/cdf651. PMC 136955. PMID 12456646.
  2. ^ a b Mosavi L, Cammett T, Desrosiers D, Peng Z (2004). . Protein Sci. 13 (6): 1435–48. doi:10.1110/ps.03554604. PMC 2279977. PMID 15152081. Archived from the original on 2004-09-07.
  3. ^ Bork P (December 1993). "Hundreds of ankyrin-like repeats in functionally diverse proteins: mobile modules that cross phyla horizontally?". Proteins. 17 (4): 363–74. doi:10.1002/prot.340170405. PMID 8108379. S2CID 35224626.
  4. ^ Mosavi LK, Minor DL, Peng ZY (Dec 2002). "Consensus-derived structural determinants of the ankyrin repeat motif". Proc Natl Acad Sci USA. 99 (25): 16029–34. Bibcode:2002PNAS...9916029M. doi:10.1073/pnas.252537899. PMC 138559. PMID 12461176.
  5. ^ Binz HK, Amstutz P, Kohl A, et al. (May 2004). "High-affinity binders selected from designed ankyrin repeat protein libraries". Nat. Biotechnol. 22 (5): 575–82. doi:10.1038/nbt962. PMID 15097997. S2CID 1191035.
  6. ^ Parra RG, Espada R, Verstraete N, Ferreiro DU, et al. (Dec 2015). "Structural and Energetic Characterization of the Ankyrin Repeat Protein Family". PLOS Comput. Biol. 12 (11): 575–82. Bibcode:2015PLSCB..11E4659P. doi:10.1371/journal.pcbi.1004659. PMC 4687027. PMID 26691182.
  7. ^ Zhang B, Peng Z (Jun 2000). "A minimum folding unit in the ankyrin repeat protein p16(INK4)". J Mol Biol. 299 (4): 1121–32. doi:10.1006/jmbi.2000.3803. PMID 10843863.
  8. ^ Tang KS, Fersht AR, Itzhaki LS (Jan 2003). "Sequential unfolding of ankyrin repeats in tumor suppressor p16". Structure. 11 (1): 67–73. doi:10.1016/S0969-2126(02)00929-2. PMID 12517341.
  9. ^ Miller MK, Bang ML, Witt CC, et al. (Nov 2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". J Mol Biol. 333 (5): 951–64. doi:10.1016/j.jmb.2003.09.012. PMID 14583192.
  10. ^ Neville MJ, Johnstone EC, Walton RT (Jun 2004). "Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1". Hum. Mutat. 23 (6): 540–5. doi:10.1002/humu.20039. PMID 15146457. S2CID 22242611.
  11. ^ "NCBI Gene summary for DRD2". (interim reference)

External links edit

This article incorporates text from the public domain Pfam and InterPro: IPR002110

December 15, 2023
ankyrin, repeat, this, article, possibly, contains, original, research, please, improve, verifying, claims, made, adding, inline, citations, statements, consisting, only, original, research, should, removed, july, 2015, learn, when, remove, this, template, mes. This article possibly contains original research Please improve it by verifying the claims made and adding inline citations Statements consisting only of original research should be removed July 2015 Learn how and when to remove this template message The ankyrin repeat is a 33 residue motif in proteins consisting of two alpha helices separated by loops first discovered in signaling proteins in yeast Cdc10 and Drosophila Notch Domains consisting of ankyrin tandem repeats mediate protein protein interactions and are among the most common structural motifs in known proteins They appear in bacterial archaeal and eukaryotic proteins but are far more common in eukaryotes Ankyrin repeat proteins though absent in most viruses are common among poxviruses Most proteins that contain the motif have four to six repeats although its namesake ankyrin contains 24 and the largest known number of repeats is 34 predicted in a protein expressed by Giardia lamblia 2 Ankyrin repeat domainRibbon diagram of a fragment of the membrane binding domain of ankyrin R 1 IdentifiersSymbolAnkPfamPF00023InterProIPR002110SMARTSM00248PROSITEPDOC50088SCOP21awc SCOPe SUPFAMAvailable protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryPDB1a5e 1ap7 1awc 1bd8 1bi7 1bi8 1blx 1bu9 1d9s 1dc2 1dcq 1g3n 1ihb 1ikn 1ixv 1k1a 1k1b 1k3z 1mx2 1mx4 1mx6 1myo 1n11 1nfi 1ot8 1oy3 1qym 1s70 1svc 1sw6 1tr4 1uoh 1wdy 1wfu 1wg0 1ycs 1yyh 1zlm 2a5e 2f8x 2f8y 2he0 2myo Ankyrin repeats typically fold together to form a single linear solenoid structure called ankyrin repeat domains These domains are one of the most common protein protein interaction platforms in nature They occur in a large number of functionally diverse proteins mainly from eukaryotes The few known examples from prokaryotes and viruses may be the result of horizontal gene transfers 3 The repeat has been found in proteins of diverse function such as transcriptional initiators cell cycle regulators cytoskeletal ion transporters and signal transducers The ankyrin fold appears to be defined by its structure rather than its function since there is no specific sequence or structure that is universally recognised by it Considering the atomic structures of individual ankyrin repeats the loop is often a type 1 beta bulge loop while both alpha helices commonly have a Schellman loop at their N terminus Contents 1 Role in protein folding 2 Clinical significance 2 1 Human proteins containing this repeat 3 See also 4 References 5 External linksRole in protein folding editThe ankyrin repeat sequence motif has been studied using multiple sequence alignment to determine conserved amino acid residues critical for folding and stability The residues on the wide lateral surface of ankyrin repeat structures are variable often hydrophobic and involved mainly in mediating protein protein interactions An artificial protein design based on a consensus sequence derived from sequence alignment has been synthesized and found to fold stably representing the first designed protein with multiple repeats 4 More extensive design strategies have used combinatorial sequences to evolve ankyrin repeats that recognize particular protein targets a technique that has been presented as an alternative to antibody design for applications requiring high affinity binding 5 A structure based study involving a range of ankyrin proteins of known structures shows that consensus based ankyrin proteins are very stable since they maximize the energetic gap between the folding and unfolding structures encoding a densely connected network of favourable interactions among conserved sequence motifs like the TPLX motif 6 The same study shows that insertions in the canonical framework of ankyrin repeats are enriched in conflictive interactions that are related to function The same applies to interactions surrounding deletion hotspots These might be related to complex folding unfolding transitions that are important to the partner recognition and interaction Ankyrin repeat proteins present an unusual problem in the study of protein folding which has largely focused on globular proteins that form well defined tertiary structure stabilized by long range nonlocal residue residue contacts Ankyrin repeats by contrast contain very few such contacts that is they have a low contact order Most studies have found that ankyrin repeats fold in a two state folding mechanism suggesting a high degree of folding cooperativity despite the local inter residue contacts and the evident need for successful folding with varying numbers of repeats Some evidence based on synthesis of truncated versions of natural repeat proteins 7 and on the examination of phi values 8 suggests that the C terminus forms the folding nucleation site Clinical significance editAnkyrin repeat proteins have been associated with a number of human diseases These proteins include the cell cycle inhibitor p16 which is associated with cancer and the Notch protein a key component of cell signalling pathways which can cause the neurological disorder CADASIL when the repeat domain is disrupted by mutations 2 A specialized family of ankyrin proteins known as muscle ankyrin repeat proteins MARPs are involved with the repair and regeneration of muscle tissue following damage due to injury and stress 9 A natural variation between glutamine and lysine at position 703 in the 11th ankyrin repeat of ANKK1 known as the TaqI A1 allele 10 has been credited with encouraging addictive behaviours such as obesity alcoholism nicotine dependency and the Eros love style citation needed while discouraging juvenile delinquency and neuroticism anxiety 11 failed verification The variation may affect the specificity of protein interactions made by the ANKK1 protein kinase through this repeat citation needed Human proteins containing this repeat edit ABTB1 ABTB2 ACBD6 ACTBL1 ANK1 ANK2 ANK3 ANKAR ANKDD1A ANKEF1 ANKFY1 ANKHD1 ANKIB1 ANKK1 ANKMY1 ANKMY2 ANKRA2 ANKRD1 ANKRD10 ANKRD11 ANKRD12 ANKRD13 ANKRD13A ANKRD13B ANKRD13C ANKRD13D ANKRD15 ANKRD16 ANKRD17 ANKRD18A ANKRD18B ANKRD19 ANKRD2 ANKRD20A1 ANKRD20A2 ANKRD20A3 ANKRD20A4 ANKRD21 ANKRD22 ANKRD23 ANKRD24 ANKRD25 ANKRD26 ANKRD27 ANKRD28 ANKRD30A ANKRD30B ANKRD30BL ANKRD32 ANKRD33 ANKRD35 ANKRD36 ANKRD36B ANKRD37 ANKRD38 ANKRD39 ANKRD40 ANKRD41 ANKRD42 ANKRD43 ANKRD44 ANKRD45 ANKRD46 ANKRD47 ANKRD49 uk ANKRD50 ANKRD52 ANKRD53 ANKRD54 ANKRD55 ANKRD56 ANKRD57 ANKRD58 ANKRD60 ANKRD6 ANKRD7 ANKRD9 ANKS1A ANKS3 ANKS4B ANKS6 ANKZF1 ASB1 ASB10 ASB11 ASB12 ASB13 ASB14 ASB15 ASB16 ASB2 ASB3 ASB4 ASB5 ASB6 ASB7 ASB8 ASB9 ASZ1 BARD1 BAT4 BAT8 BCL3 BCOR BCORL1 BTBD11 CAMTA1 CAMTA2 CASKIN1 CASKIN2 CCM1 CDKN2A CDKN2B CDKN2C CDKN2D CENTB1 CENTB2 CENTB5 CENTG1 CENTG2 CENTG3 CLIP3 CLIP4 CLPB CTGLF1 CTGLF2 CTGLF3 CTGLF4 CTGLF5 CTTNBP2 DAPK1 DDEF1 DDEF2 DDEFL1 DGKI DGKZ DP58 DYSFIP1 DZANK EHMT1 EHMT2 ESPN FANK1 FEM1A FEM1B GABPB2 GIT1 GIT2 GLS GLS2 HACE1 HECTD1 IBTK ILK INVS KIDINS220 KRIT1 LRRK1 MAIL MIB1 MIB2 MPHOSPH8 MTPN MYO16 NFKB1 NFKB2 NFKBIA NFKBIB NFKBIE NFKBIL1 NFKBIL2 NOTCH1 NOTCH2 NOTCH3 NOTCH4 NRARP NUDT12 OSBPL1A OSTF1 PLA2G6 POTE14 POTE15 POTE8 PPP1R12A PPP1R12B PPP1R12C PPP1R13B PPP1R13L PPP1R16A PPP1R16B PSMD10 RAI14 RFXANK RIPK4 RNASEL SHANK1 SHANK2 SHANK3 SNCAIP TA NFKBH TEX14 TNKS TNKS2 TNNI3K TP53BP2 TRP7 TRPA1 TRPC3 TRPC4 TRPC5 TRPC6 TRPC7 TRPV1 TRPV2 TRPV3 TRPV4 TRPV5 TRPV6 UACA USH1G ZDHHC13 ZDHHC17 See also editDARPin designed ankyrin repeat protein an engineered antibody mimetic based on the structure of ankyrin repeatsReferences edit PDB 1N11 Michaely P Tomchick DR Machius M Anderson RG December 2002 Crystal structure of a 12 ANK repeat stack from human ANK1 EMBO J 21 23 6387 96 doi 10 1093 emboj cdf651 PMC 136955 PMID 12456646 a b Mosavi L Cammett T Desrosiers D Peng Z 2004 The ankyrin repeat as molecular architecture for protein recognition Protein Sci 13 6 1435 48 doi 10 1110 ps 03554604 PMC 2279977 PMID 15152081 Archived from the original on 2004 09 07 Bork P December 1993 Hundreds of ankyrin like repeats in functionally diverse proteins mobile modules that cross phyla horizontally Proteins 17 4 363 74 doi 10 1002 prot 340170405 PMID 8108379 S2CID 35224626 Mosavi LK Minor DL Peng ZY Dec 2002 Consensus derived structural determinants of the ankyrin repeat motif Proc Natl Acad Sci USA 99 25 16029 34 Bibcode 2002PNAS 9916029M doi 10 1073 pnas 252537899 PMC 138559 PMID 12461176 Binz HK Amstutz P Kohl A et al May 2004 High affinity binders selected from designed ankyrin repeat protein libraries Nat Biotechnol 22 5 575 82 doi 10 1038 nbt962 PMID 15097997 S2CID 1191035 Parra RG Espada R Verstraete N Ferreiro DU et al Dec 2015 Structural and Energetic Characterization of the Ankyrin Repeat Protein Family PLOS Comput Biol 12 11 575 82 Bibcode 2015PLSCB 11E4659P doi 10 1371 journal pcbi 1004659 PMC 4687027 PMID 26691182 Zhang B Peng Z Jun 2000 A minimum folding unit in the ankyrin repeat protein p16 INK4 J Mol Biol 299 4 1121 32 doi 10 1006 jmbi 2000 3803 PMID 10843863 Tang KS Fersht AR Itzhaki LS Jan 2003 Sequential unfolding of ankyrin repeats in tumor suppressor p16 Structure 11 1 67 73 doi 10 1016 S0969 2126 02 00929 2 PMID 12517341 Miller MK Bang ML Witt CC et al Nov 2003 The muscle ankyrin repeat proteins CARP ankrd2 Arpp and DARP as a family of titin filament based stress response molecules J Mol Biol 333 5 951 64 doi 10 1016 j jmb 2003 09 012 PMID 14583192 Neville MJ Johnstone EC Walton RT Jun 2004 Identification and characterization of ANKK1 a novel kinase gene closely linked to DRD2 on chromosome band 11q23 1 Hum Mutat 23 6 540 5 doi 10 1002 humu 20039 PMID 15146457 S2CID 22242611 NCBI Gene summary for DRD2 interim reference External links editEukaryotic Linear Motif resource motif class LIG TNKBM 1 Ankyrin repeat at the U S National Library of Medicine Medical Subject Headings MeSH This article incorporates text from the public domain Pfam and InterPro IPR002110 Retrieved from https en wikipedia org w index php title Ankyrin 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