Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses

Sadani N. Cooray, Thomas Gobbetti, Trinidad Montero-Melendez, Simon McArthur, Dawn Thompson, Adrian J. L. Clark, Roderick J. Flower, Mauro Perretti

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

Formyl-peptide receptor type 2 (FPR2), also called ALX (the lipoxin A4 receptor), conveys the proresolving properties of lipoxin A4 and annexin A1 (AnxA1) and the proinflammatory signals elicited by serum amyloid protein A and cathelicidins, among others. We tested here the hypothesis that ALX might exist as homo- or heterodimer with FPR1 or FPR3 (the two other family members) and operate in a ligand-biased fashion. Coimmunoprecipitation and bioluminescence resonance energy transfer assays with transfected HEK293 cells revealed constitutive dimerization of the receptors; significantly, AnxA1, but not serum amyloid protein A, could activate ALX homodimers. A p38/MAPK-activated protein kinase/heat shock protein 27 signaling signature was unveiled after AnxA1 application, leading to generation of IL-10, as measured in vitro (in primary monocytes) and in vivo (after i.p. injection in the mouse). The latter response was absent in mice lacking the ALX ortholog. Using a similar approach, ALX/FPR1 heterodimerization evoked using the panagonist peptide Ac2-26, identified a JNK-mediated proapoptotic path that was confirmed in primary neutrophils. These findings provide a molecular mechanism that accounts for the dual nature of ALX and indicate that agonist binding and dimerization state contribute to the conformational landscape of FPRs.

Original languageEnglish
Pages (from-to)18232-18237
Number of pages6
JournalPNAS
Volume110
Issue number45
Early online date9 Oct 2013
DOIs
Publication statusPublished - 5 Nov 2013

Keywords

  • inflammation
  • leukocyte
  • resolution signalling

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    Cooray, S. N., Gobbetti, T., Montero-Melendez, T., McArthur, S., Thompson, D., Clark, A. J. L., Flower, R. J., & Perretti, M. (2013). Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. PNAS, 110(45), 18232-18237. https://doi.org/10.1073/pnas.1308253110