The C and PH domains of CAPS constitute an effective PI(4,5)P2-binding unit essential for Ca-regulated exocytosis.

Ca-dependent activator proteins for secretion (CAPSs) are required for Ca-regulated exocytosis in neurons and neuroendocrine cells. CAPSs contain a pleckstrin homology (PH) domain that binds PI(4,5)P2-membrane. There is also a C domain residing adjacent to the PH domain, but its function remains unclear. In this study, we solved the crystal structure of the CAPS-1 CPH module. The structure showed that the C and PH tandem packs against one another mainly via hydrophobic residues. With this interaction, the CPH module exhibited enhanced binding to PI(4,5)P2-membrane compared with the isolated PH domain. In addition, we identified a new PI(4,5)P2-binding site on the C domain. Disruption of either the tight interaction between the C and PH domains or the PI(4,5)P2-binding sites on both domains significantly impairs CAPS-1 function in Ca-regulated exocytosis at the Caenorhabditis elegans neuromuscular junction (NMJ). These results suggest that the C and PH domains constitute an effective unit to promote Ca-regulated exocytosis.