{"doi":"10.1101/2024.01.24.577102","title":"Control of Munc13-1 Activity by Autoinhibitory Interactions Involving the Variable N-terminal Region","abstract":"Abstract Regulation of neurotransmitter release during presynaptic plasticity underlies varied forms of information processing in the brain. Munc13s play essential roles in release via their conserved C-terminal region, which contains a MUN domain involved SNARE complex assembly, and control multiple presynaptic plasticity processes. Munc13s also have a variable N-terminal region, which in Munc13-1 includes a calmodulin binding (CaMb) domain involved in short-term plasticity and a C 2 A domain that forms an inhibitory homodimer. The C 2 A domain is activated by forming a heterodimer with the zinc-finger domain of αRIMs, providing a link to αRIM-dependent short- and long-term plasticity. However, it is unknown how the functions of the N- and C-terminal regions are integrated, in part because of the difficulty of purifying Munc13-1 fragments containing both regions. We describe for the first time the purification of a Munc13-1 fragment spanning its entire sequence except for a flexible region between the C 2 A and CaMb domains. We show that this fragment is much less active than the Munc13-1 C-terminal region in liposome fusion assays and that its activity is strongly enhanced by the RIM2α zinc-finger domain together with calmodulin. NMR experiments show that the C 2 A and CaMb domains bind to the MUN domain and that these interactions are relieved by the RIM2α ZF domain and calmodulin, respectively. These results suggest a model whereby Munc13-1 activity in promoting SNARE complex assembly and neurotransmitter release are inhibited by interactions of the C 2 A and CaMb domains with the MUN domain that are relieved by αRIMs and calmodulin.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":493601,"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":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":815232,"name":"Victoria Esser","orcid":"0000-0002-1913-6587","position":1,"is_corresponding":false},{"id":1255497,"name":"Katarzyna Gołębiowska-Mendroch","orcid":"0009-0003-8971-8587","position":2,"is_corresponding":false},{"id":488019,"name":"Agnieszka A. Bolembach","orcid":"0000-0003-2002-642X","position":3,"is_corresponding":false},{"id":292595,"name":"Josep Rizo","orcid":"0000-0003-1773-8311","position":4,"is_corresponding":false},{"id":828609,"name":"Junjie Xu","orcid":"0000-0003-2914-9514","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:09:03.883685Z","pmid":"38328168","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":[]}