Title | Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses |
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Authors | Cooray, S.N., Gobbetti, T., Montero-Melendez, T., McArthur, S., Thompson, D., Clark, A.J.L., Flower, R.J. and Perretti, M. |
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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. |
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Journal | Proceedings of the National Academy of Sciences of the United States of America |
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Journal citation | 110 (45), pp. 18232-18237 |
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ISSN | 1091-6490 |
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Year | Nov 2013 |
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Publisher | National Academy of Sciences |
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Digital Object Identifier (DOI) | https://doi.org/10.1073/pnas.1308253110 |
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Publication dates |
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Published | Nov 2013 |
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