{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:47:04Z","timestamp":1768517224315,"version":"3.49.0"},"posted":{"date-parts":[[2024,11,15]]},"group-title":"Biophysics","reference-count":82,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM147333"],"award-info":[{"award-number":["R35GM147333"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM150716"],"award-info":[{"award-number":["R35GM150716"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\u03b1-Synuclein (\u03b1Syn), an intrinsically disordered protein implicated in Parkinson\u2019s disease, is thought to initiate aggregation by binding to cellular membranes. Previous studies suggest that anionic lipids are necessary for this binding. However, these studies largely focused on unmodified \u03b1Syn, while physiological \u03b1Syn is N-terminally acetylated (NTA). Our work challenges the long-standing paradigm that anionic lipids are necessary for \u03b1Syn binding by demonstrating that NTA diminishes \u03b1Syn\u2019s reliance on anionic membrane charge, revealing that membrane packing defects (i.e., interfacial hydrophobicity) alone can drive membrane binding. Using fluorescence microscopy and circular dichroism spectroscopy, we monitored the binding of NTA-\u03b1Syn to membrane vesicles with different lipid compositions. Phosphatidylcholine and phosphatidylserine concentrations were varied to control surface charge, while phospholipid tail unsaturation and methylation were varied to modulate lipid packing. We also formulated cholesterol-containing membranes that mimicked the lipid composition of synaptic vesicles. In these membranes, all- atom molecular dynamics simulations were used to visualize and quantify membrane packing defects. Our results demonstrate that membrane packing defects are necessary for NTA-\u03b1Syn binding and that defect-rich membranes are sufficient for NTA-\u03b1Syn binding regardless of membrane charge. These findings provide a molecular mechanism by which lipid structural properties, such as poly-unsaturation, can regulate \u03b1Syn binding to physiological membranes.<\/jats:p>","DOI":"10.1101\/2024.11.14.623669","type":"posted-content","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T21:00:23Z","timestamp":1731704423000},"source":"Crossref","is-referenced-by-count":1,"title":["Lipid Packing Defects are Necessary and Sufficient for Membrane Binding of \u03b1-Synuclein"],"prefix":"10.64898","author":[{"given":"David H.","family":"Johnson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Orianna H.","family":"Kou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie Y.","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonis","family":"Margaritakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vance W.","family":"Jaeger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2341-8923","authenticated-orcid":false,"given":"Wade F.","family":"Zeno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025052704250441000_2024.11.14.623669v3.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.08-08-02804.1988"},{"key":"2025052704250441000_2024.11.14.623669v3.2","doi-asserted-by":"publisher","DOI":"10.1038\/42166"},{"key":"2025052704250441000_2024.11.14.623669v3.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.11.6469"},{"key":"2025052704250441000_2024.11.14.623669v3.4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24065914"},{"key":"2025052704250441000_2024.11.14.623669v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2022.11.007"},{"key":"2025052704250441000_2024.11.14.623669v3.6","doi-asserted-by":"crossref","unstructured":"Sarchione, A. , Marchand, A. , Taymans, J.-M. & Chartier-Harlin, M.-C . 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