Formyl peptide receptor

Studies in the 1970s found that a series of N-formylmethionine-containing oligopeptides, including the most potent and well-known member of this series, N-formylmethionine-leucyl-phenylalanine (fMLF or fMet-Leu-Phe), stimulated rabbit and human neutrophils to migrate in a specific direction by an apparently receptor-dependent mechanism in classical laboratory chemotaxis experiments. Since these oligopeptides were produced by bacteria or synthetic analogs of such products, it was hypothesized that the N-formyl oligopeptides were important chemotactic factors and their receptors were important chemotactic factor receptors, each acting as a signaling and signal recognition element to trigger inflammatory responses to defend against bacterial invasion. Further studies defined a receptor for the N-formyl oligopeptides, the formyl peptide receptor (FPR), so named for its ability to bind to and be activated by the oligopeptides. Subsequently, two receptors were discovered and named FPR1 and FPR2 based on the similarity of the predicted amino acid sequence of their genes to that of FPR, rather than their ability to bind to or be activated by the formyl oligopeptides. These three receptors have been renamed FPR1, FPR2 and FPR3 and have very different specificities for the formyl oligopeptides and very different functions, including triggering inflammatory responses to N-formyl peptides released not only by bacteria but also by a variety of elements from host tissues, dampening and resolving inflammatory responses, and possibly contributing to the development of certain neurological cancers and a number of amyloid-based neurological diseases.

The formyl peptide receptors (FPRs:-FPR1, FPR2 and FPR3) belong to a class of G protein-coupled receptors that are involved in chemotaxis. They are encoded by separate genes of the same name (see FPR1 gene, FPR2 gene and FPR3 gene below). They are mainly expressed by mammalian phagocytic leukocytes. The FPRs receptor proteins are involved in the antibacterial defense and inflammatory reactions of the host organism.

Three isoforms of formyl peptide receptors are expressed in humans. These receptors were originally identified due to their ability to bind N-formylpeptides such as N-formylmethionine, which are produced by the degradation of bacterial or host cells, which explains their naming.

Therefore, formyl peptide receptors are involved in mediating the immune cell response to infections. Under certain conditions, these receptors can also suppress the immune system. The close phylogenetic relationship of signaling in chemotaxis and olfaction was recently demonstrated by the detection of formyl peptide receptor-like proteins as a distinct family of chemosensors in the vomeronasal organ of mice.

The formyl peptide receptor (FPR) belongs to the class of receptors with seven hydrophobic transmembrane domains. The conformation of the FPR is stabilized by several interactions. These include the possible bridging between Arg84-Arg205, Lys85-Arg205 and Lys85-Asp284, which helps to determine the three-dimensional structure of the transmembrane domains, as well as positively charged residues (Arg, Lys) that interact with negatively charged phosphates. In addition, residue Arg163 can interact with the ligand binding site of the second extracellular loop of the FPR.

The formyl-Met group of the ligand has been shown to form disulfide bridges with Cys residues, and an interaction with Arg163 has also been demonstrated. Some oligopeptides have also been described as characteristic components associated with Asn-s of the extracellular N-terminal part and with the ligand binding site of the second extracellular loop. These components may also determine the ligand-receptor interaction or make it more specific.

1. Boulay F et al. (1990) Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA. Biochem Biophys Res Commun 168:1103-1109.
2. Harada M et al. (2004) N-Formylated humanin activates both formyl peptide receptor-like 1 and 2. Biochem Biophys Res Commun 324:255-261
3. Maestes DC et al.(1999) Differential phosphorylation paradigms dictate desensitization and internalization of the N-formyl peptide receptor. J Biol Chem 274:29791-2975.
4. Murphy PM et al. (1991) Functional expression of the human formyl peptide receptor in Xenopus oocytes requires a complementary human factor. J Biol Chem 266:12560-12567.
5. Postma B et al. (2004) Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J Immunol 172:6994-7001.
6. Sun R et al. (2004) Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor. J Immunol 173:428-436.
7. Ye RD et al. (1992) Isolation of a cDNA that encodes a novel granulocyte N-formyl peptide receptor. Biochem Biophys Res Commun184:582-589