{"doi":"10.3390/ijms21124410","title":"Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes","abstract":"<jats:p>Stromal interaction molecule 1 (STIM1) is a ubiquitously expressed Ca2+ sensor protein that induces permeation of Orai Ca2+ channels upon endoplasmic reticulum Ca2+-store depletion. A drop in luminal Ca2+ causes partial unfolding of the N-terminal STIM1 domains and thus initial STIM1 activation. We compared the STIM1 structure upon Ca2+ depletion from our molecular dynamics (MD) simulations with a recent 2D NMR structure. Simulation- and structure-based results showed unfolding of two α-helices in the canonical and in the non-canonical EF-hand. Further, we structurally and functionally evaluated mutations in the non-canonical EF-hand that have been shown to cause tubular aggregate myopathy. We found these mutations to cause full constitutive activation of Ca2+-release-activated Ca2+ currents (ICRAC) and to promote autophagic processes. Specifically, heterologously expressed STIM1 mutations in the non-canonical EF-hand promoted translocation of the autophagy transcription factors microphthalmia-associated transcription factor (MITF) and transcription factor EB (TFEB) into the nucleus. These STIM1 mutations additionally stimulated an enhanced production of autophagosomes. In summary, mutations in STIM1 that cause structural unfolding promoted Ca2+ down-stream activation of autophagic processes.</jats:p>","journal":"International Journal of Molecular Sciences","year":2020,"id":29183,"datarank":0.8410260287101081,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.33084642146078475,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.33084642146078475,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":17,"citers_with_citation_signal":15,"citers_with_endowment":15,"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":161524,"name":"Adéla Tiffner","orcid":"0000-0002-7529-4504","position":1,"is_corresponding":false},{"id":161525,"name":"Tony 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Sallinger","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"32575830","pmcid":"PMC7352373","openalex_id":"https://openalex.org/W3036770067","authors":[],"funders":[{"funder_name":"Austrian Science Fund","grant_id":"P28701","title":"Calcium domain in Orai1 regulates NFAT dependent genes"},{"funder_name":"Austrian Science Fund","grant_id":"P32075-B","title":null},{"funder_name":"Austrian Science Fund","grant_id":"P28821-B27","title":null},{"funder_name":"Austrian Science Fund","grant_id":"P27641","title":null},{"funder_name":"Austrian Science Fund","grant_id":"P30567","title":null},{"funder_name":"Austrian Science Fund","grant_id":"P32851","title":null},{"funder_name":"Linz Institute of 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Channels and Receptors","Postharvest Quality and Shelf Life Management","Plant Stress Responses and Tolerance","Chemistry","Medicine","Biology","0301 basic medicine","03 medical and health sciences","0303 health sciences","Autophagy","Calcium","Cations, Divalent","EF Hand Motifs","Humans","Molecular Dynamics Simulation","Mutation","Myopathies, Structural, Congenital","Neoplasm Proteins","Protein Conformation, alpha-Helical","Protein Unfolding","Stromal Interaction Molecule 1"],"mesh_terms":["Stromal Interaction Molecule 1","Protein Conformation, alpha-Helical","Autophagy","Calcium","Cations, Divalent","Humans","Mutation","Neoplasm Proteins","EF Hand Motifs","Myopathies, Structural, Congenital","Molecular Dynamics Simulation","Protein Unfolding"],"keywords":["STIM1","Endoplasmic reticulum","Cell biology","Chemistry","Autophagy","Mutant","Transcription factor","Biophysics","Biochemistry","Biology","Gene","Ca2+","Mitf","Orai","Stim","Ef-hand","Tfeb","Soce","Hydrophobic Pocket","Tubular 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