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Ca<jats:sup>2+<\/jats:sup> induces synaptotagmin-1 binding to its own vesicle membrane, called the <jats:italic>cis-<\/jats:italic>interaction, thus preventing the <jats:italic>trans<\/jats:italic>-interaction of synaptotagmin-1 to the plasma membrane. However, the electrostatic regulation of the <jats:italic>cis<\/jats:italic>- and <jats:italic>trans<\/jats:italic>-membrane interaction of synaptotagmin-1 was poorly understood in different Ca<jats:sup>2+<\/jats:sup>-buffering conditions. Here we provide an assay to monitor the <jats:italic>cis<\/jats:italic>- and <jats:italic>trans<\/jats:italic>-membrane interactions of synaptotagmin-1 by using native purified vesicles and the plasma membrane-mimicking liposomes (PM-liposomes). Both ATP and EGTA similarly reverse the <jats:italic>cis<\/jats:italic>-membrane interaction of synaptotagmin-1 in free [Ca<jats:sup>2+<\/jats:sup>] of 10\u2013100\u00a0\u03bcM. High PIP<jats:sub>2<\/jats:sub> concentrations in the PM-liposomes reduce the Hill coefficient of vesicle fusion and synaptotagmin-1 membrane binding; this observation suggests that local PIP<jats:sub>2<\/jats:sub> concentrations control the Ca<jats:sup>2+<\/jats:sup>-cooperativity of synaptotagmin-1. Our data provide evidence that Ca<jats:sup>2+<\/jats:sup> chelators, including EGTA and polyphosphate anions such as ATP, ADP, and AMP, electrostatically reverse the <jats:italic>cis<\/jats:italic>-interaction of synaptotagmin-1.<\/jats:p>","DOI":"10.1038\/s41598-022-26723-9","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T10:04:29Z","timestamp":1672135469000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Electrostatic regulation of the cis- and trans-membrane interactions of synaptotagmin-1"],"prefix":"10.1038","volume":"12","author":[{"given":"Houda Yasmine","family":"Ali Moussa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongsoo","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,12,27]]},"reference":[{"key":"26723_CR1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1038\/nrm2002","volume":"7","author":"R Jahn","year":"2006","unstructured":"Jahn, R. & Scheller, R. 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