{"doi":"10.1101/2023.06.20.545669","title":"Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes","abstract":"Summary Tomosyns are soluble SNARE proteins proposed to attenuate membrane fusion by competing with synaptobrevin-2/VAMP2 for SNARE-complex assembly. Here, we present evidence against this scenario using a novel mouse model, energy barrier recordings, and single-molecule force measurements. Tomosyn-1/2 deficiency drastically enhanced the probability that synaptic vesicles fuse at synapses, resulting in stronger synapses with faster depression and slower recovery. While wildtype tomosyn-1m rescued these phenotypes, substitution of its SNARE motif with that of synaptobrevin-2/VAMP2 did not. Force measurements revealed that tomosyn’s SNARE motif cannot substitute synaptobrevin-2/VAMP2 to form template complexes with Munc18-1 and syntaxin-1, an essential intermediate for SNARE assembly. Instead, tomosyns bind synaptobrevin-2/VAMP2-containing template complexes and prevent SNAP-25 association. Structure-function analyses indicate that regions outside the SNARE motif contribute to tomosyn’s inhibitory function. These results reveal that tomosyns regulate synaptic transmission by preventing SNAP-25 binding to template complexes, increasing the energy barrier for synaptic vesicle fusion, and limiting synaptic depression.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":408958,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":806628,"name":"Miriam Öttl","orcid":"0000-0001-6435-4658","position":1,"is_corresponding":false},{"id":331462,"name":"Jie Yang","orcid":"0000-0002-3522-0906","position":2,"is_corresponding":false},{"id":293046,"name":"Aygul Subkhangulova","orcid":"0000-0001-8843-0678","position":3,"is_corresponding":false},{"id":750050,"name":"Avinash Kumar","orcid":"0000-0001-6184-3069","position":4,"is_corresponding":false},{"id":1188458,"name":"Alexander J. Groffen","orcid":"0000-0003-0046-4027","position":5,"is_corresponding":false},{"id":1188459,"name":"Jan R.T. van Weering","orcid":"0000-0001-5259-4945","position":6,"is_corresponding":false},{"id":331464,"name":"Yongli Zhang","orcid":"0000-0001-7079-7973","position":7,"is_corresponding":false},{"id":65645,"name":"Matthijs Verhage","orcid":"0000-0002-6085-7503","position":8,"is_corresponding":false},{"id":806630,"name":"Marieke Meijer","orcid":"0000-0001-6873-3807","position":0,"is_corresponding":true}],"reference_count":117,"raw_metadata":null,"created_at":"2026-07-19T01:21:22.368387Z","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":[]}