{"doi":"10.1091/mbc.e07-05-0498","title":"A Novel Site of Action for α-SNAP in the SNARE Conformational Cycle Controlling Membrane Fusion","abstract":"<jats:p>Regulated exocytosis in neurons and neuroendocrine cells requires the formation of a stable soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex consisting of synaptobrevin-2/vesicle-associated membrane protein 2, synaptosome-associated protein of 25 kDa (SNAP-25), and syntaxin 1. This complex is subsequently disassembled by the concerted action of α-SNAP and the ATPases associated with different cellular activities-ATPase N-ethylmaleimide-sensitive factor (NSF). We report that NSF inhibition causes accumulation of α-SNAP in clusters on plasma membranes. Clustering is mediated by the binding of α-SNAP to uncomplexed syntaxin, because cleavage of syntaxin with botulinum neurotoxin C1 or competition by using antibodies against syntaxin SNARE motif abolishes clustering. Binding of α-SNAP potently inhibits Ca<jats:sup>2+</jats:sup>-dependent exocytosis of secretory granules and SNARE-mediated liposome fusion. Membrane clustering and inhibition of both exocytosis and liposome fusion are counteracted by NSF but not when an α-SNAP mutant defective in NSF activation is used. We conclude that α-SNAP inhibits exocytosis by binding to the syntaxin SNARE motif and in turn prevents SNARE assembly, revealing an unexpected site of action for α-SNAP in the SNARE cycle that drives exocytotic membrane fusion.</jats:p>","journal":"Molecular Biology of the Cell","year":2008,"id":666550,"datarank":0.5897738449086489,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"self_citation_contribution":0.5897738449086489,"citation_network_contribution":0.0,"self_endowment_contribution":0.5897738449086489,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1740673,"name":"John J. 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This complex is subsequently disassembled by the concerted action of α-SNAP and the ATPases associated with different cellular activities-ATPase N-ethylmaleimide-sensitive factor (NSF). We report that NSF inhibition causes accumulation of α-SNAP in clusters on plasma membranes. Clustering is mediated by the binding of α-SNAP to uncomplexed syntaxin, because cleavage of syntaxin with botulinum neurotoxin C1 or competition by using antibodies against syntaxin SNARE motif abolishes clustering. Binding of α-SNAP potently inhibits Ca<jats:sup>2+</jats:sup>-dependent exocytosis of secretory granules and SNARE-mediated liposome fusion. Membrane clustering and inhibition of both exocytosis and liposome fusion are counteracted by NSF but not when an α-SNAP mutant defective in NSF activation is used. We conclude that α-SNAP inhibits exocytosis by binding to the syntaxin SNARE motif and in turn prevents SNARE assembly, revealing an unexpected site of action for α-SNAP in the SNARE cycle that drives exocytotic membrane fusion.</jats:p>","is_dataset_classified":null,"base_score":3.9318256327243257,"endowment":3.9318256327243257,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"18094056","pmcid":"PMC2262999","openalex_id":"https://openalex.org/W2161358208","authors":[],"funders":[],"total_grants":0,"fwci":1.4574,"citation_percentile":0.80363168,"influential_citations":0,"citation_trend":[{"year":2012,"count":2},{"year":2013,"count":3},{"year":2014,"count":4},{"year":2015,"count":2},{"year":2016,"count":4},{"year":2017,"count":3},{"year":2018,"count":1},{"year":2019,"count":1},{"year":2020,"count":1},{"year":2021,"count":4},{"year":2023,"count":1},{"year":2024,"count":1},{"year":2025,"count":1},{"year":2026,"count":3}],"oa_status":"green","license":"other-oa","oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2262999","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2262999","host_type":"repository"},{"url":"https://doi.org/10.1091/mbc.e07-05-0498","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/18094056","host_type":"repository"},{"url":"http://edoc.mpg.de/357037","host_type":"repository"},{"url":"http://hdl.handle.net/11858/00-001M-0000-0012-DCBF-7","host_type":"repository"}],"fields_of_study":["Cellular transport and secretion","Lipid Membrane Structure and Behavior","Retinal Development and Disorders","Amino Acid Motifs","Animals","Binding Sites","Calcium","Cell Membrane","Cell-Free System","Exocytosis","Humans","Membrane Fusion","Models, Biological","N-Ethylmaleimide-Sensitive Proteins","PC12 Cells","Protein Conformation","Protein Transport","Rats","SNARE Proteins","Secretory Vesicles","Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins","Syntaxin 1"],"mesh_terms":["Animals","Binding Sites","Calcium","Cell Membrane","Cell-Free System","Exocytosis","Humans","Membrane Fusion","Models, Biological","Protein Conformation","PC12 Cells","Amino Acid Motifs","Protein Transport","Secretory Vesicles","SNARE Proteins","Syntaxin 1","Rats","N-Ethylmaleimide-Sensitive Proteins","Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins"],"keywords":["Syntaxin","Exocytosis","SNARE complex","Synaptobrevin","Biology","Munc-18","Cell biology","Lipid bilayer fusion","STX1A","Vesicle fusion","SNAP25","Syntaxin 3","Vesicle","Biochemistry","Synaptic vesicle","Secretion","Membrane"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-13T14:47:47.538934Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}