Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding.

Communications Biology
Bill X HuangHee-Yong Kim

Abstract

Adhesion G protein-coupled receptors (aGPCR) are characterized by a large extracellular region containing a conserved GPCR-autoproteolysis-inducing (GAIN) domain. Despite their relevance to several disease conditions, we do not understand the molecular mechanism by which aGPCRs are physiologically activated. GPR110 (ADGRF1) was recently deorphanized as the functional receptor of N-docosahexaenoylethanolamine (synaptamide), a potent synaptogenic metabolite of docosahexaenoic acid. Thus far, synaptamide is the first and only small-molecule endogenous ligand of an aGPCR. Here, we demonstrate the molecular basis of synaptamide-induced activation of GPR110 in living cells. Using in-cell chemical cross-linking/mass spectrometry, computational modeling and mutagenesis-assisted functional assays, we discover that synaptamide specifically binds to the interface of GPR110 GAIN subdomains through interactions with residues Q511, N512 and Y513, causing an intracellular conformational change near TM6 that triggers downstream signaling. This ligand-induced GAIN-targeted activation mechanism provides a framework for understanding the physiological function of aGPCRs and therapeutic targeting in the GAIN domain.

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Citations

Aug 9, 2020·The Journal of Biological Chemistry·Alexander VizurragaGregory G Tall
Apr 4, 2021·International Journal of Molecular Sciences·Heungsun KwonHee-Yong Kim
Jun 11, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Noor Mazin AbdulkareemMeghana V Trivedi
Jul 21, 2021·Biochemical Society Transactions·Matthew RosaGraham Ladds

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Methods Mentioned

BETA
X-ray
nuclear magnetic resonance
co-immunoprecipitation
co-immnoprecipitatation
scraping
transfection
Confocal microscopy
immunoprecipitation

Software Mentioned

Mascot Distiller
TASSER
Progenesis QI for Proteomics
PSIPRED
Proteome Discovery
Progenesis QI
PSI
xQuest
MOE
CLUSTALW

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