{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T06:53:28Z","timestamp":1768287208822,"version":"3.49.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013604","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000}}],"reference-count":126,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R33-AI101387"],"award-info":[{"award-number":["R33-AI101387"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004175","name":"Orta Do\u00c4\u0178u Teknik \u00c3\u0153niversitesi","doi-asserted-by":"publisher","award":["METU-BAP TEZ-YL-108-2022-10856"],"award-info":[{"award-number":["METU-BAP TEZ-YL-108-2022-10856"]}],"id":[{"id":"10.13039\/501100004175","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Botulinum Neurotoxin Serotype A (BoNT\/A), responsible for most human botulism cases, inhibits neurotransmitter release by cleaving the target protein SNAP-25. Previous literature demonstrated that BoNT\/A mediated cleavage of a small subset of the SNAP-25 pool, resulting in SNAP-25 (1\u2013197) fragments, is sufficient to block exocytosis. SNAP-25 (1\u2013197) potentially competes against intact SNAP-25 for SNARE complexes and blocks neurotransmission through a dominant-negative mechanism. However, how a tiny fraction of cleaved SNAP-25 efficiently outcompetes a large pool of intact SNAP-25 remains unknown. Here, we examined the importance of SNAP-25 phosphorylation at Ser187 residue, located in the C-terminus SNARE domain, in the context of BoNT action. Our results demonstrated that Ser187-phosphorylated SNAP-25 can be efficiently cleaved in cells. Importantly, BoNT\/A-cleaved SNAP-25 fragments in neuronal and non-neuronal cells are heavily phosphorylated at Ser187 and localized on the cell membrane. SNAP-25 (1\u2013197) binds to syntaxin-1A, and the interaction is enhanced by Ser187 phosphorylation. We also found that SNAP-25 (1\u2013197) survives longer than the BoNT\/A enzymatic component itself in cells. Molecular modeling suggested that SNAP-25 (1\u2013197), phosphorylated or not, forms stable SNARE complexes; however, Ser187 phosphorylation induces local changes in surface electrostatic potential and dynamics of the complex. This study characterizes the molecular mechanism underlying the dominant-negative effect of SNAP-25 (1\u2013197) on neurotransmission. This research could have implications for the future development of BoNT\/A inhibitors and the generation of new BoNT\/A clinical formulations by regulating the abundance of Ser187 phosphorylation in cleaved SNAP-25 fragments.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013604","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T17:45:09Z","timestamp":1760463909000},"page":"e1013604","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phosphorylation of SNAP-25 at Ser187 is enhanced following its cleavage by Botulinum Neurotoxin Serotype A, promoting the dominant-negative effect of the resulting fragment"],"prefix":"10.1371","volume":"21","author":[{"given":"Dilara","family":"Koc","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sena","family":"Ezgin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ebru","family":"Kavakli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krishna P.","family":"Kota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edanur","family":"Sen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Mahone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary Ellen","family":"Palko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa 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