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

136 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

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Annexin A1
Formyl Peptide Receptor
Serum Amyloid A Protein
Dimerization
G-Protein-Coupled Receptors
Lipoxin Receptors
Cathelicidins
HSP27 Heat-Shock Proteins
Ligands
Annexins
HEK293 Cells
Energy Transfer
p38 Mitogen-Activated Protein Kinases
Interleukin-10
Protein Kinases
Monocytes
Neutrophils
Injections
lipoxin A4
annexin A1 peptide (2-26)

Keywords

  • inflammation
  • leukocyte
  • resolution signalling

Cite this

Cooray, S. N., Gobbetti, T., Montero-Melendez, T., McArthur, S., Thompson, D., Clark, A. J. L., ... 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

Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. / Cooray, Sadani N.; Gobbetti, Thomas; Montero-Melendez, Trinidad; McArthur, Simon; Thompson, Dawn; Clark, Adrian J. L.; Flower, Roderick J.; Perretti, Mauro.

In: PNAS, Vol. 110, No. 45, 05.11.2013, p. 18232-18237.

Research output: Contribution to journalArticle

Cooray, SN, Gobbetti, T, Montero-Melendez, T, McArthur, S, Thompson, D, Clark, AJL, Flower, RJ & Perretti, M 2013, 'Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses', PNAS, vol. 110, no. 45, pp. 18232-18237. https://doi.org/10.1073/pnas.1308253110
Cooray, Sadani N. ; Gobbetti, Thomas ; Montero-Melendez, Trinidad ; McArthur, Simon ; Thompson, Dawn ; Clark, Adrian J. L. ; Flower, Roderick J. ; Perretti, Mauro. / Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. In: PNAS. 2013 ; Vol. 110, No. 45. pp. 18232-18237.
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AU - Thompson, Dawn

AU - Clark, Adrian J. L.

AU - Flower, Roderick J.

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