{"doi":"10.1016/j.celrep.2022.111408","title":"Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3","abstract":"The AAA+ protein, Skd3 (human CLPB), solubilizes proteins in the mitochondrial intermembrane space, which is critical for human health. Skd3 variants with defective protein-disaggregase activity cause severe congenital neutropenia (SCN) and 3-methylglutaconic aciduria type 7 (MGCA7). How Skd3 disaggregates proteins remains poorly understood. Here, we report a high-resolution structure of a Skd3-substrate complex. Skd3 adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers. Deleting the ANK linker region reduces dodecamerization and disaggregase activity. We elucidate apomorphic features of the Skd3 NBD and C-terminal domain that regulate disaggregase activity. We also define how Skd3 subunits collaborate to disaggregate proteins. Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. These advances illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns, and suggest therapeutic strategies.","journal":"Cell Reports","year":2022,"id":252107,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":108134,"name":"Alexandrea N. Rizo","orcid":"0000-0003-4813-6348","position":1,"is_corresponding":false},{"id":896060,"name":"Gabriel A. Braun","orcid":"0000-0002-9105-5757","position":2,"is_corresponding":false},{"id":227715,"name":"Eric Tse","orcid":"0000-0002-2082-9006","position":3,"is_corresponding":false},{"id":492659,"name":"Edward Chuang","orcid":"0000-0002-6380-7317","position":4,"is_corresponding":false},{"id":361197,"name":"Kushol Gupta","orcid":"0000-0002-7006-2667","position":5,"is_corresponding":false},{"id":565763,"name":"Daniel R. Southworth","orcid":"0000-0001-7108-9389","position":6,"is_corresponding":false},{"id":268287,"name":"James Shorter","orcid":"0000-0001-5269-8533","position":7,"is_corresponding":false},{"id":302139,"name":"Ryan R. Cupo","orcid":"0000-0001-7639-1923","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T00:24:46.226372Z","pmid":"36170828","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":[]}