Formyl peptide receptor

Last updated

formyl peptide receptor 1
Identifiers
SymbolFPR1
Alt. symbolsFPR; FMLP
NCBI gene 2357
HGNC 3826
OMIM 136537
RefSeq NM_002029
UniProt P21462
Other data
Locus Chr. 19 q13.41
Search for
Structures Swiss-model
Domains InterPro
formyl peptide receptor 2
Identifiers
SymbolFPR2
Alt. symbolsALXR, FMLPX, FPR2/ALX, FPR2A, FPRH1, FPRL1, HM63, LXA4R, RFP
NCBI gene 2358
HGNC 3827
OMIM 136538
RefSeq NM_001462
UniProt P25090
Other data
Locus Chr. 19 q13.3-13.4
Search for
Structures Swiss-model
Domains InterPro
formyl peptide receptor 3
Identifiers
SymbolFPR3
Alt. symbolsFPRH2, FPRL2, FMLPY
NCBI gene 2359
HGNC 3828
OMIM 136539
RefSeq NM_002030
UniProt P25089
Other data
Locus Chr. 19 q13.3-13.4
Search for
Structures Swiss-model
Domains InterPro

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]

Contents

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

Discovery

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

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]

Signaling pathways

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:

See also

References

  1. 1 2 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. 1 2 3 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. 1 2 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.