@article{c8e272b4fcd34a7cbdb4f2f5c8cb891a,
title = "Synaptotagmin C2A Loop 2 mediates Ca2+-dependent SNARE interactions essential for Ca2+-triggered vesicle exocytosis",
abstract = "Synaptotagmins contain tandem C2 domains and function as Ca2+ sensors for vesicle exocytosis but the mechanism for coupling Ca2+ rises to membrane fusion remains undefined. Synaptotagmins bind SNAREs, essential components of the membrane fusion machinery, but the role of these interactions in Ca2+-triggered vesicle exocytosis has not been directly assessed. We identified sites on synaptotagmin-1 that mediate Ca 2+-dependent SNAP25 binding by zero-length cross-linking. Mutation of these sites in C2A and C2B eliminated Ca2+-dependent synaptotagmin-1 binding to SNAREs without affecting Ca2+-dependent membrane binding. The mutants failed to confer Ca2+ regulation on SNARE-dependent liposome fusion and failed to restore Ca2+-triggered vesicle exocytosis in synaptotagmin-deficient PC12 cells. The results provide direct evidence that Ca2+-dependent SNARE binding by synaptotagmin is essential for Ca2+-triggered vesicle exocytosis and that Ca 2+-dependent membrane binding by itself is insufficient to trigger fusion. A structure-based model of the SNARE-binding surface of C2A provided a new view of how Ca2+-dependent SNARE and membrane binding occur simultaneously.",
author = "Lynch, {K. L.} and Gerona, {R. R.L.} and Larsen, {E. C.} and Marcia, {R. F.} and Mitchell, {J. C.} and Martin, {T. F.J.}",
year = "2007",
month = dec,
doi = "10.1091/mbc.E07-04-0368",
language = "English",
volume = "18",
pages = "4957--4968",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
number = "12",
}