Formylpeptide receptors: Introduction

Initial discoveries

Bacterial protein synthesis is initiated with an N-Formylmethionine (fMet) at the amino terminus [29]. This feature of prokaryotic protein synthesis is used by mammalian immune cells to recognize the invading bacteria. Receptors that bind formylpeptides were initially found in phagocytes from humans and rabbits [22,28]. Formylpeptides containing as few as 3 amino acids (e.g. fMet-Leu-Phe, fMLF) are potent chemoattractants for human and rabbit neutrophils [18]. These peptides are able to induce chemotaxis, degranulation and superoxide production, which are important bactericidal functions [16,31]. The human genome contains 3 genes coding for a subfamily of G protein-coupled receptors (GPCRs) termed the formylpeptide receptors (FPRs). Human FPR1 gene was isolated using a radiolabeled formylpeptide derivative [2-3]. The genes for FPR2 and FPR3 were both identified using homology-based cloning [1,21,23,32]. As a result, these two receptors were also termed formylpeptide receptor-like 1 (FPRL1) and -like 2 (FPRL2), respectively. In mice, the Fpr subfamily consists of 8 different members, 3 of which being similar to the human counterparts based on their protein sequence and expression profile [31].

Functional roles

FPRs interact with a diverse collection of ligands and are among the most promiscuous GPCRs known to date [31]. The primary function of FPR1 is recognition of formylpeptides. Bacterial formylpeptides that activate FPR1 include fMLF from E. coli [18], fMIFL from S. aureus [27], and fMIVIL from L. monocytogenes [25,30]. Mouse Fpr1 (mFpr1) binds fMLF with low affinity, but responds well to longer peptides including fMIFL and fMIVIL [30]. Genetic deletion of mFpr1 compromises immunity against Listeria infection [10], confirming an important role of the receptor in host defense. In addition to binding bacterial formylpeptides, FPR1 recognizes mitochondrial peptides bearing the fMet at their N-termini [4]. This function is critical to phagocyte response to acute tissue injury [19,33], which leads to clearance of cell debris and initiation of tissue repair.

FPR2 was initially identified as having low affinity for fMLF [21,32]. Subsequent studies show that it prefers formylpeptides with certain lengths and amino acid composition, e.g., fMMYALF [25]. Computer modeling combined with site-directed mutagenesis has shown that the binding pocket of FPR2 differs from the one in FPR1 [14]. This may explain why FPR2 is able to interact with a variety of ligands with different structures, including virus-derived peptides, annexin A1, serum amyloid A, the cathelicidin LL-37, synthetic peptides such as WKYMVm and MMK-1, and small molecules including Quin-C1 and Compound 43 (reviewed in [31]). Deletion of mFpr2 compromises immunity against L. monocytogenes infection [17]. mFpr2 has been shown to play a role in colonic epithelial cell homeostasis, inflammation and tumorigenesis [5].

Another line of work focuses on FPR2 interaction with lipid mediators including lipoxin A4 (LXA4) [8] and resolvin D1 (RvD1) [15]. It has been reported that LXA4, at picomolar to low nanomolar concentrations, is able to activate FPR2 and trigger anti-inflammatory actions (reviewed in [6]). The lipid mediators as well as annexin A1 may interact with FPR2 homo- or hetero-dimers for the anti-inflammatory effects [7]. However, other investigators have not been able to replicate the receptor-activating and δ-arrestin-recruiting functions of LXA4 through FPR2 [9,11,24]. A joint effort between the FPR Subcommittee and Leukotriene Receptors Subcommittee is under way to resolve the experimental discrepancy.

Compared to FPR1 and FPR2, much less is known about the pharmacological properties of FPR3. This receptor binds to formylated peptides and proteins such as humanin better than the non-formylated version [12]. F2L, an acetylated N-terminal fragment of heme-binding protein, has been identified as an endogenous ligand for FPR3 [20]. FPR3 was undetectable on the surface of monocytes from a small number of healthy donors [20]. In transfected cells, FPR3 and mFpr3 are found mostly inside the cells [13,26]. The exact mechanism of FPR3 expression is not fully understood.

Nomenclature issues

The FPR subfamily of GPCRs was initially identified based on the interaction with formylpeptides, hence the name formylpeptide receptors. However, when the FPR Subcommittee of NC-IUPHAR was charged with the task of FPR nomenclature, one of the receptors, FPR2, was already given the name ALX (for lipoxin A4) by the Leukotriene Receptors Subcommittee [6]. Although the majority of the FPR Subcommittee members proposed the name FPR2, a combined name FPR2/ALX was eventually adopted and has been in use since 2009. At present, the FPR Subcommittee has been working with the Leukotriene Receptors Subcommittee to address questions raised by laboratories that could not reproduce the reported G protein-activating functions of LXA4 [8]. This site will be updated when the results become available.

Future prospects

The FPRs have one of the most diverse collections of ligands amongst all GPCRs; they also mediate broad cellular functions ranging from chemotaxis to superoxide generation. Future studies will focus on the structural basis for FPR interaction with different ligands, as well as the signaling mechanisms resulting from receptor activation and leading to effector functions. As new ligands for the FPRs continue to be identified, this site will be updated periodically to keep up with the current status of FPR research. Reader feedback will be greatly appreciated.


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