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.
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http://dx.doi.org/10.1016/j.str.2023.02.004 | DOI Listing |
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