Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands.

He, Hui; Troksa, Erica L.; Caltabiano, Gianluigi; Pardo, Leonardo; Ye, Richard D.

doi:10.1074/jbc.a113.509216

Cited by 7 publications

(8 citation statements)

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“…S3). The position of one of these differentially conserved amino acids (His106) was previously identified by modeling approaches as likely having a role in ligand recognition by Fprs (17). To evaluate the selective pressures acting on the immune and the vomeronasal Fprs, we then calculated pairwise K a /K s ratios [the rate of nonsynonymous substitutions (K a ) over the rate of synonymous substitutions (K s )] for Fpr-rs3, Fpr-rs2, and Fpr1 of the different rodent species.…”

Section: Resultsmentioning

confidence: 99%

Evolution of immune chemoreceptors into sensors of the outside world

Dietschi

Tuberosa

Rösingh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Changes in gene expression patterns represent an essential source of evolutionary innovation. A striking case of neofunctionalization is the acquisition of neuronal specificity by immune formyl peptide receptors (Fprs). In mammals, Fprs are expressed by immune cells, where they detect pathogenic and inflammatory chemical cues. In rodents, these receptors are also expressed by sensory neurons of the vomeronasal organ, an olfactory structure mediating innate avoidance behaviors. Here we show that two gene shuffling events led to two independent acquisitions of neuronal specificity by Fprs. The first event targeted the promoter of a V1R receptor gene. This was followed some 30 million years later by a second genomic accident targeting the promoter of a V2R gene. Finally, we show that expression of a vomeronasal Fpr can reverse back to the immune system under inflammatory conditions via the production of an intergenic transcript linking neuronal and immune Fpr genes. Thus, three hijackings of regulatory elements are sufficient to explain all aspects of the complex expression patterns acquired by a receptor family that switched from sensing pathogens inside the organism to sensing the outside world through the nose.olfaction | vomeronasal organ | olfactory receptor | gene evolution | neofunctionalization

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Section: Resultsmentioning

confidence: 99%

Evolution of immune chemoreceptors into sensors of the outside world

Dietschi

Tuberosa

Rösingh

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The amino acids of the N-terminus in PSMα2 1-16 are identical to those in PSMα2 1-5 and PSMα2 1-10 , respectively, yet the peptides activate different receptors. It is known from earlier studies that the binding pocket in FPR1 has room for no more than five amino acids [15], and when the charge of an FPR1 selective pentapeptide is reduced, such peptides will interact also with FPR2 [31], even if FPR1 is still the preferred receptor [32]. This means that receptor preference is not determined solely by the amino acids that have access to the presumed agonist binding pocket of the receptor, but in part also by amino acids in the peptide that do not have direct access to the binding pocket.…”

Section: Discussionmentioning

confidence: 99%

“…Receptor mutagenesis studies with FPR1 suggest that amino acids in both extracellular and transmembrane domains are of importance for agonist binding [10,12,14,33], but only a limited number of these (i.e., the ones in positions 84, 85, 89, 90 102, and 103) differ between FPR1 and FPR2. Recent computer modeling and site directed mutagenesis experiments have suggested that the amino acid difference in position 281 (an Asp in FPR2 and a Gly in FPR1) is of importance for the selectivity in agonist binding [32], and an exchange of the Asp in FPR2 for a Gly may change the activation potency of certain fMet containing peptides [32]. The chimeric receptor approach has also been used to define the molecular determinants involved in agonist recognition [5,6], and it is evident that an exchange of receptor parts that are not directly involved in agonist binding may also affect the selectivity.…”

Section: Discussionmentioning

confidence: 99%

Structural changes of the ligand and of the receptor alters the receptor preference for neutrophil activating peptides starting with a formylmethionyl group

Forsman

Winther

Gabl

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Pathogenic Staphylococcus aureus strains produce N-formylmethionyl containing peptides, of which the tetrapeptide fMIFL is a potent activator of the neutrophil formyl peptide receptor 1 (FPR1) and the PSMα2 peptide is a potent activator of the closely related FPR2. Variants derived from these two peptide activators were used to disclose the structural determinants for receptor interaction. Removal of five amino acids from the C-terminus of PSMα2 gave rise to a peptide that had lost the receptor-independent neutrophil permeabilizing effect, whereas neutrophil activation capacity as well as its preference for FPR2 was retained. Shorter peptides, PSMα21-10 and PSMα21-5, activate neutrophils, but the receptor preference for these peptides was switched to FPR1. The fMIFL-PSM5-16 peptide, in which the N-terminus of PSMα21-16 was replaced by the sequence fMIFL, was a dual agonist for FPR1/FPR2, whereas fMIFL-PSM5-10 preferred FPR1 to FPR2. Further, an Ile residue was identified as a key determinant for interaction with FPR2. A chimeric receptor in which the cytoplasmic tail of FPR1 was replaced by the corresponding part of FPR2 lost the ability to recognize FPR1 agonists, but gained function in relation to FPR2 agonists. Taken together, our data demonstrate that the C-terminus of the PSMα2 peptide plays a critical role for its cytotoxicity, but is not essential for the receptor-mediated pro-inflammatory activity. More importantly, we show that the amino acids present in the C-terminus, which are not supposed to occupy the agonist-binding pocket in the FPRs, are of importance for the choice of receptor.

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“…40 It was one of the first descriptions of a receptor capable of binding lipids, peptides, and proteins with ligands including serum amyloid A, lipoxin A 4 , and AnnA1 and has been reviewed in detail elsewhere. 9,37,61 Importantly, these ligand-specific interactions are able to induce either proinflammatory or proresolution/anti-inflammatory effects.…”

Section: Formyl Peptide Receptormentioning

confidence: 99%

The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation

Dorward

Lucas

Chapman

et al. 2015

The American Journal of Pathology

210

200

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Neutrophil migration to sites of inflammation and the subsequent execution of multiple functions are designed to contain and kill invading pathogens. These highly regulated and orchestrated processes are controlled by interactions between numerous receptors and their cognate ligands. Unraveling and identifying those that are central to inflammatory processes may represent novel therapeutic targets for the treatment of neutrophil-dominant inflammatory disorders in which dysregulated neutrophil recruitment, function, and elimination serve to potentiate rather than resolve an initial inflammatory insult. The first G protein-coupled receptor to be described on human neutrophils, formyl peptide receptor 1 (FPR1), is one such receptor that plays a significant role in the execution of these functions through multiple intracellular signaling pathways. Recent work has highlighted important observations with regard to both receptor function and the importance and functional relevance of FPR1 in the pathogenesis of a range of both sterile and infective inflammatory conditions. In this review, we explore the multiple components of neutrophil migration and function in both health and disease, with a focus on the role of FPR1 in these processes. The current understanding of FPR1 structure, function, and signaling is examined, alongside discussion of the potential importance of FPR1 in inflammatory diseases suggesting that FPR1 is a key regulator of the inflammatory environment.

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Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands.

Cited by 7 publications

References 0 publications

Evolution of immune chemoreceptors into sensors of the outside world

Evolution of immune chemoreceptors into sensors of the outside world

Structural changes of the ligand and of the receptor alters the receptor preference for neutrophil activating peptides starting with a formylmethionyl group

The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation

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