{"doi":"10.1016/j.celrep.2019.12.077","title":"Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants","abstract":"Increased calpain activity is linked to neuroinflammation including a heritable retinal disease caused by hyper-activating mutations in the calcium-activated calpain-5 (CAPN5) protease. Although structures for classical calpains are known, the structure of CAPN5, a non-classical calpain, remains undetermined. Here we report the 2.8 Å crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical calpains, CAPN5-PC requires high calcium concentrations for maximal activity. Structure-based phylogenetic analysis and multiple sequence alignment reveal that CAPN5-PC contains three elongated flexible loops compared to its classical counterparts. The presence of a disease-causing mutation (c.799G>A, p.Gly267Ser) on the unique PC2L2 loop reveals a function in this region for regulating enzymatic activity. This mechanism could be transferred to distant calpains, using synthetic calpain hybrids, suggesting an evolutionary mechanism for fine-tuning calpain function by modifying flexible loops. Further, the open (inactive) conformation of CAPN5-PC provides structural insight into CAPN5-specific residues that can guide inhibitor design.","journal":"Cell Reports","year":2020,"id":102075,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9352,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":499043,"name":"Young Joo Sun","orcid":"0000-0002-8240-7378","position":1,"is_corresponding":false},{"id":499044,"name":"S. Khan","orcid":"0000-0002-3604-2670","position":2,"is_corresponding":false},{"id":371908,"name":"Jing Yang","orcid":"0000-0002-8984-4503","position":3,"is_corresponding":false},{"id":427426,"name":"Jonathan Herrmann","orcid":null,"position":4,"is_corresponding":false},{"id":372994,"name":"Teja Chemudupati","orcid":null,"position":5,"is_corresponding":false},{"id":499045,"name":"Robert E. MacLaren","orcid":"0000-0002-3096-4682","position":6,"is_corresponding":false},{"id":499046,"name":"Lokesh Gakhar","orcid":"0000-0002-3319-1902","position":7,"is_corresponding":false},{"id":271805,"name":"Soichi Wakatsuki","orcid":"0000-0001-5896-7968","position":8,"is_corresponding":false},{"id":285420,"name":"Alexander G. Bassuk","orcid":"0000-0002-4067-2157","position":9,"is_corresponding":false},{"id":317223,"name":"Vinit B. Mahajan","orcid":"0000-0003-1886-1741","position":10,"is_corresponding":false},{"id":317221,"name":"Gabriel Velez","orcid":"0000-0003-0819-5933","position":0,"is_corresponding":true}],"reference_count":90,"raw_metadata":null,"created_at":"2026-07-18T22:40:51.552773Z","pmid":"31968260","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":[]}