{"doi":"10.1021/acs.biochem.4c00223","title":"Pathogenic R<sub>163</sub>W Variant of the Copper Chaperone for Sod1 (Ccs) Functions as an Anti-chaperone","abstract":"The copper chaperone for Sod1 (Ccs) is a metallochaperone that plays a multifaceted role in the maturation of Cu,Zn superoxide dismutase (Sod1). The Ccs mutation R 163 W was identified in an infant with fatal neurological abnormalities. Based on a comprehensive structural and functional analysis, we developed the first data-driven model for R 163 W-related pathogenic phenotypes. The work here confirms previous findings that the substitution of arginine with tryptophan at this site, which is located adjacent to a conserved Zn binding site, creates an unstable Zn-deficient protein that loses its ability to efficiently activate Sod1. Intriguingly, R 163 W Ccs can reduce copper (i.e., Cu(II) → Cu(I)) bound in its Sod1-like domain (D2), and this novel redox event is accompanied by disulfide bond formation. The loss of Zn binding, along with the unusual ability to bind copper in D2, diverts R 163 W Ccs toward aggregation. The remarkably high affinity of D2 Cu(I) binding converts R 163 W from a Cu chaperone to a Cu scavenger that accelerates Sod1 deactivation (i.e., an Anti-chaperone). Overall, these findings present a first-of-its-kind molecular mechanism for Ccs dysfunction that leads to pathogenesis in humans.","journal":"Biochemistry","year":2024,"id":451638,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9422,"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":310579,"name":"Stefanie D. Boyd","orcid":"0000-0002-7018-2730","position":1,"is_corresponding":false},{"id":1273507,"name":"Dannie Zhabilov","orcid":null,"position":2,"is_corresponding":false},{"id":312788,"name":"Morgan S. Ullrich","orcid":null,"position":3,"is_corresponding":false},{"id":564520,"name":"Ninian J. Blackburn","orcid":"0000-0002-9755-7838","position":4,"is_corresponding":false},{"id":310580,"name":"Duane D. Winkler","orcid":"0000-0003-1045-0323","position":5,"is_corresponding":false},{"id":439920,"name":"Bei Zhang","orcid":"0000-0002-4602-5524","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:02:45.951080Z","pmid":"39099176","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":[]}