TY - JOUR
T1 - The C2 and PH domains of CAPS constitute an effective PI(4,5)P2-binding unit essential for Ca2+-regulated exocytosis
AU - Zhang, Li
AU - Li, Lei
AU - Wei, Ziqing
AU - Zhou, Hao
AU - Liu, Haowen
AU - Wang, Shen
AU - Ren, Yijing
AU - Dai, Tiankai
AU - Wang, Jiafan
AU - Hu, Zhitao
AU - Ma, Cong
PY - 2023/4/6
Y1 - 2023/4/6
N2 - Ca2+-dependent activator proteins for secretion (CAPSs) are required for Ca2+-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 C2 domain residing adjacent to the PH domain, but its function remains unclear. In this study, we solved the crystal structure of the CAPS-1 C2PH module. The structure showed that the C2 and PH tandem packs against one another mainly via hydrophobic residues. With this interaction, the C2PH 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 C2 domain. Disruption of either the tight interaction between the C2 and PH domains or the PI(4,5)P2-binding sites on both domains significantly impairs CAPS-1 function in Ca2+-regulated exocytosis at the Caenorhabditis elegans neuromuscular junction (NMJ). These results suggest that the C2 and PH domains constitute an effective unit to promote Ca2+-regulated exocytosis. © 2023 Elsevier Ltd.
AB - Ca2+-dependent activator proteins for secretion (CAPSs) are required for Ca2+-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 C2 domain residing adjacent to the PH domain, but its function remains unclear. In this study, we solved the crystal structure of the CAPS-1 C2PH module. The structure showed that the C2 and PH tandem packs against one another mainly via hydrophobic residues. With this interaction, the C2PH 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 C2 domain. Disruption of either the tight interaction between the C2 and PH domains or the PI(4,5)P2-binding sites on both domains significantly impairs CAPS-1 function in Ca2+-regulated exocytosis at the Caenorhabditis elegans neuromuscular junction (NMJ). These results suggest that the C2 and PH domains constitute an effective unit to promote Ca2+-regulated exocytosis. © 2023 Elsevier Ltd.
KW - CAPS
KW - exocytosis
KW - PI(4,5)P2
KW - SNARE
UR - http://www.scopus.com/inward/record.url?scp=85150831984&partnerID=8YFLogxK
UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85150831984&origin=recordpage
U2 - 10.1016/j.str.2023.02.004
DO - 10.1016/j.str.2023.02.004
M3 - RGC 21 - Publication in refereed journal
C2 - 36863339
SN - 0969-2126
VL - 31
SP - 424-434.e6
JO - Structure
JF - Structure
IS - 4
ER -