The DID of CAPS-1 anchors plasma membrane to promote vesicle exocytosis

Ca²⁺-dependent activator proteins for secretion are multidomain proteins involved in Ca²⁺-regulated exocytosis of synaptic vesicles and dense core vesicles. Ca²⁺-dependent activator proteins for secretion contain a dynactin1-interacting domain (DID), previously implicated in vesicle sorting. Here, we reveal a novel role for the DID in direct membrane association. Using structural modeling, liposome binding, and fusion assays, we demonstrate that the DID binds to and clusters negatively charged phospholipids, such as phosphatidylserine and phosphatidylinositol 4,5-bisphosphate, and significantly enhances SNARE-mediated liposome fusion. Furthermore, deletion of the DID in PC12 cells impairs evoked vesicle release. Our findings establish the DID as a critical plasma membrane-anchoring module that promotes efficient vesicle exocytosis.