{"doi":"10.1016/j.celrep.2020.108611","title":"SNARE Zippering Is Suppressed by a Conformational Constraint that Is Removed by v-SNARE Splitting","abstract":"Intracellular vesicle fusion is catalyzed by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Vesicle-anchored v-SNAREs pair with target membrane-associated t-SNAREs to form trans-SNARE complexes, releasing free energy to drive membrane fusion. However, trans-SNARE complexes are unable to assemble efficiently unless activated by Sec1/Munc18 (SM) proteins. Here, we demonstrate that SNAREs become fully active when the v-SNARE is split into two fragments, eliminating the requirement of SM protein activation. Mechanistically, v-SNARE splitting accelerates the zippering of trans-SNARE complexes, mimicking the stimulatory function of SM proteins. Thus, SNAREs possess the full potential to drive efficient membrane fusion but are suppressed by a conformational constraint. This constraint is removed by SM protein activation or v-SNARE splitting. We suggest that ancestral SNAREs originally evolved to be fully active in the absence of SM proteins. Later, a conformational constraint coevolved with SM proteins to achieve the vesicle fusion specificity demanded by complex endomembrane systems.","journal":"Cell Reports","year":2021,"id":175059,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":274722,"name":"Chun Wan","orcid":"0000-0002-8827-0552","position":1,"is_corresponding":false},{"id":715378,"name":"Shailendra S. Rathore","orcid":"0000-0001-7290-3645","position":2,"is_corresponding":false},{"id":246040,"name":"Michael H. B. Stowell","orcid":"0000-0001-7250-1419","position":3,"is_corresponding":false},{"id":404461,"name":"Haijia Yu","orcid":"0000-0002-7193-8034","position":4,"is_corresponding":false},{"id":274723,"name":"Jingshi Shen","orcid":"0000-0001-9595-1148","position":5,"is_corresponding":false},{"id":715377,"name":"Yinghui Liu","orcid":"0000-0002-4717-2147","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-18T23:47:11.249697Z","pmid":"33440145","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":[]}