Munc13 Homology Domain-1 in CAPS/UNC31 Mediates SNARE Binding Required for Priming Vesicle Exocytosis

Neuropeptide and peptide hormone secretion from neural and endocrine cells occurs by Ca 2+-triggered dense-core vesicle exocytosis. The membrane fusion machinery consisting of vesicle and plasma membrane SNARE proteins needs to be assembled for Ca 2+-triggered vesicle exocytosis. The related Munc13 and CAPS/UNC31 proteins that prime vesicle exocytosis are proposed to promote SNARE complex assembly. CAPS binds SNARE proteins and stimulates SNARE complex formation on liposomes, but the relevance of SNARE binding to CAPS function in cells had not been determined. Here we identify a core SNARE-binding domain in CAPS as corresponding to Munc13 homology domain-1 (MHD1). CAPS lacking a single helix in MHD1 was unable to bind SNARE proteins or to support the Ca 2+-triggered exocytosis of either docked or newly arrived dense-core vesicles. The results show that MHD1 is a SNARE-binding domain and that SNARE protein binding is essential for CAPS function in dense-core vesicle exocytosis. [Display omitted] ► CAPS is required for a late step in Ca 2+-triggered dense-core vesicle exocytosis ► CAPS binding to SNARE proteins is mediated by a DAMH (DUF1041-MHD1) domain ► CAPS lacking a helix in MHD1 exhibited impaired activity in vesicle exocytosis ► MHD1 is a core SNARE-binding domain utilized in priming vesicle exocytosis