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Formyl peptide receptor

January 01, 1970

The formyl peptide receptors (FPR) belong to a class of G protein-coupled receptors involved in chemotaxis.[1][2] In humans, there are three formyl peptide receptor isoforms, each encoded by a separate gene that are named FPR1, FPR2, and FPR3.[1] These receptors were originally identified by their ability to bind N-formyl peptides such as N-formylmethionine produced by the degradation of either bacterial or host cells.[3][4] Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions.[5] The close phylogenetic relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ chemosensors in mice.[6][7]

formyl peptide receptor 1
Identifiers
SymbolFPR1
Alt. symbolsFPR; FMLP
NCBI gene2357
HGNC3826
OMIM136537
RefSeqNM_002029
UniProtP21462
Other data
LocusChr. 19 q13.41
Search for
StructuresSwiss-model
DomainsInterPro
formyl peptide receptor 2
Identifiers
SymbolFPR2
Alt. symbolsALXR, FMLPX, FPR2/ALX, FPR2A, FPRH1, FPRL1, HM63, LXA4R, RFP
NCBI gene2358
HGNC3827
OMIM136538
RefSeqNM_001462
UniProtP25090
Other data
LocusChr. 19 q13.3-13.4
Search for
StructuresSwiss-model
DomainsInterPro
formyl peptide receptor 3
Identifiers
SymbolFPR3
Alt. symbolsFPRH2, FPRL2, FMLPY
NCBI gene2359
HGNC3828
OMIM136539
RefSeqNM_002030
UniProtP25089
Other data
LocusChr. 19 q13.3-13.4
Search for
StructuresSwiss-model
DomainsInterPro

FPR is now properly accepted as termed FPR1 by the International Union of Basic and Clinical Pharmacology.[2]

Discovery edit

Studies conducted in the 1970s found that a series of N-Formylmethionine-containing oligopeptides, including the most potent and best known member of this series, N-formylmethionine-leucyl-phenylalanine (fMLF or fMet-Leu-Phe), stimulated rabbit and human neutrophils by an apparent receptor-dependent mechanism to migrate in a directional pattern in classical laboratory assays of chemotaxis. Since these oligopeptides were produced by bacteria or synthetic analogs of such products, it was suggested that the N-formyl oligopeptides are important chemotatic factors and their receptors are important chemotactic factor receptors that act respectively as signaling and signal-recognizing elements to initiate inflammation responses in order to defend against bacterial invasion. Further studies defined a receptor for the N-formyl oligopeptides, formyl peptide receptor (FPR), so named based on its ability to bind and become activated by the oligopeptides. Two receptors where thereafter discovered and named FPR1 and FPR2 based on the similarity of their genes' predicted amino acid sequence to that of FPR rather than on any ability to bind or be activated by the formyl oligopeptides. These three receptors have been renamed as FPR1, FPR2, and FPR3 and found to have very different specificities for the formyl oligopeptides and very different functions that include initiating inflammatory responses to N-formyl peptides released not only by bacteria but also a multiplicity of elements released by host tissues; dampening and resolving inflammatory responses; and perhaps contributing to the development of certain neurological cancers and an array of neurological diseases Amyloid-based diseases.[2]

Structure and function edit

The formyl peptide receptor (FPR) belongs to the class of receptors possessing seven hydrophobic transmembrane domains. The conformation of the FPR is stabilized by several interactions. These include potential salt bridge formation between Arg84-Arg205, Lys85-Arg205, and Lys85-Asp284 which help determine the three-dimensional structure of transmembrane domains, as well as positively charged residues (Arg, Lys) which interact with negatively charged phosphates. Furthermore, residue Arg163 may interact with the ligand binding pocket of the second extracellular loop of the FPR.

With respect to binding of the formyl Met-Leu-Phe peptide, there are additional potential interactions which include hydrogen bonding interactions between Arg84 and Lys85 of the first extracellular loop and the N-formyl group of the ligand as well as the peptide backbone of formyl Met-Leu-Phe which can form similar interactions. The formyl-Met moiety of the ligand was shown to form disulfide bridges with Cys residues, and an interaction with Arg163 was also demonstrated. (It is important to mention that some interaction which stabilize the conformation of the receptor may also influence ligand-binding.) Some oligopeptides were also described as characteristic constituents linked to Asn-s of the extracellular N terminal part and to the ligand binding pocket of the second extracellular loop. These components can also determine or make more specific the ligand-receptor interaction.[7][8]

  •  
    Schematic diagram of the formyl peptide receptor 1. Transmembrane helices of the receptor are represented by blue-green cylinders while the cell membrane in which the receptor is imbedded is depicted in yellow. The extracellular face of the cell membrane is on top while the intracellular (cytoplasmic) face is on the bottom. Extracellular loops of the FPR responsible for N-for-Met-Leu-Phe (Nfor-MLF) binding are shown in red.
  •  
    Formyl peptide receptor (FPR) signaling pathways.

Signaling pathways edit

Induction of FPR triggers multiple changes in eukaryotic cells including rearrangement of the cytoskeleton which in turn facilitates cell migration and the synthesis of chemokines. Important FPR regulated pathways include:

  • G protein dependent activation of phospholipase C (PLC) which results in the breakdown of the membrane constituent phospholipid, phosphatidylinositol (4,5)-bisphosphate (PIP2) into inositol (1,4,5)-trisphosphate (IP3) and diacyl glycerol (DAG). IP3 is one of the most effective inducers of Ca2+ increase from cytoplasmic pools and from outside the cell via opening Ca2+ channels. DAG in turn is an inducer of protein kinase C (PKC).
  • Activation of the regulatory small GTPase, RAS. The active RAS can in turn activate RAF, a Ser/Thr kinase. In the next step mitogen-activated protein kinases (MAP kinases) are activated. (Also known as extracellular signal-regulated kinases - ERKs or MAP/ERK kinase (MEK)). As a result of the last step, ERK1 and ERK2 are activated. The phosphorylated forms of ERKs can continue the cascade by triggering activation more interacting kinases which results in altered transcriptional activity in the nucleus.
  • Ligand binding to FPR can also induce the activation of CD38, an ectoenzyme of the surface membrane. As a result of activation NAD+ molecules will enter the cytoplasm. NAD+ is converted into cyclic ADP ribose (cADPR), a second messenger which interacts with ryanodine receptors (RyR) on the surface of the rough endoplasmic reticulum. The overall result of the process is increased cytoplasmic Ca2+ levels via the direct pathway described above and also via indirect pathways such as opening of Ca2+ channels in the cell membrane. The sustained increase of Ca2+ is required for directed migration of the cells.[9]

See also edit

References edit

  1. ^ a b Migeotte I, Communi D, Parmentier M (Dec 2006). "Formyl peptide receptors: a promiscuous subfamily of G protein-coupled receptors controlling immune responses". Cytokine & Growth Factor Reviews. 17 (6): 501–19. doi:10.1016/j.cytogfr.2006.09.009. PMID 17084101.
  2. ^ a b c Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM (Jun 2009). "International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family". Pharmacological Reviews. 61 (2): 119–61. doi:10.1124/pr.109.001578. PMC 2745437. PMID 19498085.
  3. ^ Le Y, Murphy PM, Wang JM (Nov 2002). "Formyl-peptide receptors revisited". Trends in Immunology. 23 (11): 541–8. doi:10.1016/S1471-4906(02)02316-5. PMID 12401407.
  4. ^ Panaro MA, Acquafredda A, Sisto M, Lisi S, Maffione AB, Mitolo V (2006). "Biological role of the N-formyl peptide receptors". Immunopharmacology and Immunotoxicology. 28 (1): 103–27. doi:10.1080/08923970600625975. hdl:11586/115781. PMID 16684671. S2CID 23082578.
  5. ^ Braun MC, Wang JM, Lahey E, Rabin RL, Kelsall BL (Jun 2001). "Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes". Blood. 97 (11): 3531–6. doi:10.1182/blood.V97.11.3531. PMID 11369647.
  6. ^ Rivière S, Challet L, Fluegge D, Spehr M, Rodriguez I (May 2009). "Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors". Nature. 459 (7246): 574–7. Bibcode:2009Natur.459..574R. doi:10.1038/nature08029. PMID 19387439. S2CID 4302009.
  7. ^ a b Yuan S, Ghoshdastider U, Trzaskowski B, Latek D, Debinski A, Pulawski W, Wu R, Gerke V, Filipek S (2012). "The role of water in activation mechanism of human N-formyl peptide receptor 1 (FPR1) based on molecular dynamics simulations". PLOS ONE. 7 (11): e47114. Bibcode:2012PLoSO...747114Y. doi:10.1371/journal.pone.0047114. PMC 3506623. PMID 23189124.
  8. ^ Lala A, Gwinn M, De Nardin E (Sep 1999). "Human formyl peptide receptor function role of conserved and nonconserved charged residues". European Journal of Biochemistry. 264 (2): 495–9. doi:10.1046/j.1432-1327.1999.00647.x. PMID 10491096.
  9. ^ Partida-Sánchez S, Cockayne DA, Monard S, Jacobson EL, Oppenheimer N, Garvy B, Kusser K, Goodrich S, Howard M, Harmsen A, Randall TD, Lund FE (Nov 2001). "Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo". Nature Medicine. 7 (11): 1209–16. doi:10.1038/nm1101-1209. PMID 11689885. S2CID 13239085.

External links edit

  • . IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-06-19. Retrieved 2007-11-02.
  • Formyl+peptide+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

January 01, 1970
formyl, peptide, receptor, formyl, peptide, receptors, belong, class, protein, coupled, receptors, involved, chemotaxis, humans, there, three, formyl, peptide, receptor, isoforms, each, encoded, separate, gene, that, named, fpr1, fpr2, fpr3, these, receptors, . The formyl peptide receptors FPR belong to a class of G protein coupled receptors involved in chemotaxis 1 2 In humans there are three formyl peptide receptor isoforms each encoded by a separate gene that are named FPR1 FPR2 and FPR3 1 These receptors were originally identified by their ability to bind N formyl peptides such as N formylmethionine produced by the degradation of either bacterial or host cells 3 4 Hence formyl peptide receptors are involved in mediating immune cell response to infection These receptors may also act to suppress the immune system under certain conditions 5 The close phylogenetic relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ chemosensors in mice 6 7 formyl peptide receptor 1IdentifiersSymbolFPR1Alt symbolsFPR FMLPNCBI gene2357HGNC3826OMIM136537RefSeqNM 002029UniProtP21462Other dataLocusChr 19 q13 41Search forStructuresSwiss modelDomainsInterPro formyl peptide receptor 2IdentifiersSymbolFPR2Alt symbolsALXR FMLPX FPR2 ALX FPR2A FPRH1 FPRL1 HM63 LXA4R RFPNCBI gene2358HGNC3827OMIM136538RefSeqNM 001462UniProtP25090Other dataLocusChr 19 q13 3 13 4Search forStructuresSwiss modelDomainsInterPro formyl peptide receptor 3IdentifiersSymbolFPR3Alt symbolsFPRH2 FPRL2 FMLPYNCBI gene2359HGNC3828OMIM136539RefSeqNM 002030UniProtP25089Other dataLocusChr 19 q13 3 13 4Search forStructuresSwiss modelDomainsInterPro FPR is now properly accepted as termed FPR1 by the International Union of Basic and Clinical Pharmacology 2 Contents 1 Discovery 2 Structure and function 3 Signaling pathways 4 See also 5 References 6 External linksDiscovery editStudies conducted in the 1970s found that a series of N Formylmethionine containing oligopeptides including the most potent and best known member of this series N formylmethionine leucyl phenylalanine fMLF or fMet Leu Phe stimulated rabbit and human neutrophils by an apparent receptor dependent mechanism to migrate in a directional pattern in classical laboratory assays of chemotaxis Since these oligopeptides were produced by bacteria or synthetic analogs of such products it was suggested that the N formyl oligopeptides are important chemotatic factors and their receptors are important chemotactic factor receptors that act respectively as signaling and signal recognizing elements to initiate inflammation responses in order to defend against bacterial invasion Further studies defined a receptor for the N formyl oligopeptides formyl peptide receptor FPR so named based on its ability to bind and become activated by the oligopeptides Two receptors where thereafter discovered and named FPR1 and FPR2 based on the similarity of their genes predicted amino acid sequence to that of FPR rather than on any ability to bind or be activated by the formyl oligopeptides These three receptors have been renamed as FPR1 FPR2 and FPR3 and found to have very different specificities for the formyl oligopeptides and very different functions that include initiating inflammatory responses to N formyl peptides released not only by bacteria but also a multiplicity of elements released by host tissues dampening and resolving inflammatory responses and perhaps contributing to the development of certain neurological cancers and an array of neurological diseases Amyloid based diseases 2 Structure and function editThe formyl peptide receptor FPR belongs to the class of receptors possessing seven hydrophobic transmembrane domains The conformation of the FPR is stabilized by several interactions These include potential salt bridge formation between Arg84 Arg205 Lys85 Arg205 and Lys85 Asp284 which help determine the three dimensional structure of transmembrane domains as well as positively charged residues Arg Lys which interact with negatively charged phosphates Furthermore residue Arg163 may interact with the ligand binding pocket of the second extracellular loop of the FPR With respect to binding of the formyl Met Leu Phe peptide there are additional potential interactions which include hydrogen bonding interactions between Arg84 and Lys85 of the first extracellular loop and the N formyl group of the ligand as well as the peptide backbone of formyl Met Leu Phe which can form similar interactions The formyl Met moiety of the ligand was shown to form disulfide bridges with Cys residues and an interaction with Arg163 was also demonstrated It is important to mention that some interaction which stabilize the conformation of the receptor may also influence ligand binding Some oligopeptides were also described as characteristic constituents linked to Asn s of the extracellular N terminal part and to the ligand binding pocket of the second extracellular loop These components can also determine or make more specific the ligand receptor interaction 7 8 nbsp Schematic diagram of the formyl peptide receptor 1 Transmembrane helices of the receptor are represented by blue green cylinders while the cell membrane in which the receptor is imbedded is depicted in yellow The extracellular face of the cell membrane is on top while the intracellular cytoplasmic face is on the bottom Extracellular loops of the FPR responsible for N for Met Leu Phe Nfor MLF binding are shown in red nbsp Formyl peptide receptor FPR signaling pathways Signaling pathways editInduction of FPR triggers multiple changes in eukaryotic cells including rearrangement of the cytoskeleton which in turn facilitates cell migration and the synthesis of chemokines Important FPR regulated pathways include G protein dependent activation of phospholipase C PLC which results in the breakdown of the membrane constituent phospholipid phosphatidylinositol 4 5 bisphosphate PIP2 into inositol 1 4 5 trisphosphate IP3 and diacyl glycerol DAG IP3 is one of the most effective inducers of Ca2 increase from cytoplasmic pools and from outside the cell via opening Ca2 channels DAG in turn is an inducer of protein kinase C PKC Activation of the regulatory small GTPase RAS The active RAS can in turn activate RAF a Ser Thr kinase In the next step mitogen activated protein kinases MAP kinases are activated Also known as extracellular signal regulated kinases ERKs or MAP ERK kinase MEK As a result of the last step ERK1 and ERK2 are activated The phosphorylated forms of ERKs can continue the cascade by triggering activation more interacting kinases which results in altered transcriptional activity in the nucleus Ligand binding to FPR can also induce the activation of CD38 an ectoenzyme of the surface membrane As a result of activation NAD molecules will enter the cytoplasm NAD is converted into cyclic ADP ribose cADPR a second messenger which interacts with ryanodine receptors RyR on the surface of the rough endoplasmic reticulum The overall result of the process is increased cytoplasmic Ca2 levels via the direct pathway described above and also via indirect pathways such as opening of Ca2 channels in the cell membrane The sustained increase of Ca2 is required for directed migration of the cells 9 See also editChemotaxis ReceptorsReferences edit a b Migeotte I Communi D Parmentier M Dec 2006 Formyl peptide receptors a promiscuous subfamily of G protein coupled receptors controlling immune responses Cytokine amp Growth Factor Reviews 17 6 501 19 doi 10 1016 j cytogfr 2006 09 009 PMID 17084101 a b c Ye RD Boulay F Wang JM Dahlgren C Gerard C Parmentier M Serhan CN Murphy PM Jun 2009 International Union of Basic and Clinical Pharmacology LXXIII Nomenclature for the formyl peptide receptor FPR family Pharmacological Reviews 61 2 119 61 doi 10 1124 pr 109 001578 PMC 2745437 PMID 19498085 Le Y Murphy PM Wang JM Nov 2002 Formyl peptide receptors revisited Trends in Immunology 23 11 541 8 doi 10 1016 S1471 4906 02 02316 5 PMID 12401407 Panaro MA Acquafredda A Sisto M Lisi S Maffione AB Mitolo V 2006 Biological role of the N formyl peptide receptors Immunopharmacology and Immunotoxicology 28 1 103 27 doi 10 1080 08923970600625975 hdl 11586 115781 PMID 16684671 S2CID 23082578 Braun MC Wang JM Lahey E Rabin RL Kelsall BL Jun 2001 Activation of the formyl peptide receptor by the HIV derived peptide T 20 suppresses interleukin 12 p70 production by human monocytes Blood 97 11 3531 6 doi 10 1182 blood V97 11 3531 PMID 11369647 Riviere S Challet L Fluegge D Spehr M Rodriguez I May 2009 Formyl peptide receptor like proteins are a novel family of vomeronasal chemosensors Nature 459 7246 574 7 Bibcode 2009Natur 459 574R doi 10 1038 nature08029 PMID 19387439 S2CID 4302009 a b Yuan S Ghoshdastider U Trzaskowski B Latek D Debinski A Pulawski W Wu R Gerke V Filipek S 2012 The role of water in activation mechanism of human N formyl peptide receptor 1 FPR1 based on molecular dynamics simulations PLOS ONE 7 11 e47114 Bibcode 2012PLoSO 747114Y doi 10 1371 journal pone 0047114 PMC 3506623 PMID 23189124 Lala A Gwinn M De Nardin E Sep 1999 Human formyl peptide receptor function role of conserved and nonconserved charged residues European Journal of Biochemistry 264 2 495 9 doi 10 1046 j 1432 1327 1999 00647 x PMID 10491096 Partida Sanchez S Cockayne DA Monard S Jacobson EL Oppenheimer N Garvy B Kusser K Goodrich S Howard M Harmsen A Randall TD Lund FE Nov 2001 Cyclic ADP ribose production by CD38 regulates intracellular calcium release extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo Nature Medicine 7 11 1209 16 doi 10 1038 nm1101 1209 PMID 11689885 S2CID 13239085 External links edit Formylpeptide Receptors IUPHAR Database of Receptors and Ion Channels International Union of Basic and Clinical Pharmacology Archived from the original on 2015 06 19 Retrieved 2007 11 02 Formyl peptide receptor at the U S National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Formyl peptide receptor amp oldid 1216311125, wikipedia, wiki, book, books, 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