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The molecular requirements for the G protein betagamma‐SNARE interaction

Inhibitory G‐protein coupled receptors (GPCRs) can attenuate the secretion of hormones and neurotransmitters in an Ca2+‐dependent fashion. It has been shown that one mechanism for this inhibition involves the direct interaction of G‐protein βγ dimers (Gβγ) with the soluble N‐ethylmaleimide sensitive attachment protein receptor (SNARE) proteins syntaxin1A (Stx1A) and SNAP‐25. We have previously shown that Gβγ competes with the calcium sensor synaptotagmin 1 (Syt1) for binding sites upon SNARE proteins in a Ca2+ dependent manner. The goal of this study is to determine the individual residues required for the Gβγ‐SNARE interaction. To investigate the molecular basis for this interaction, prior studies performed by our group utilizing a “peptide mapping” approach have shown that both the N‐terminal and the C‐terminal domains of SNAP‐25 are essential for the interaction of Gβγ with SNAP‐25. Here, utilizing a similar approach, we demonstrate that the N‐terminal Habc domain is essential for the interaction of Gβγ with Stx1A. The interaction is mediated through two positively‐charged residues: K55 and R125. Mutation of these residues to Ala abolishes Gβγ binding in vitro, while retaining the ability to bind Syt1. We anticipate that these studies will enhance our understanding of the GPCR‐mediated regulatory mechanisms of exocytosis.