ArticleCell reports2022
Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.
Article in Cell reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- HAX1 drives assembly and activation of the mitochondrial intermembrane space chaperone CLPB.bioRxiv : the preprint server for biology · 2026Article
- Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice.Theranostics · 2026Article
- Quality control at the powerhouse: mitochondrial proteostasis dysfunction and disease.Biochemical Society transactions · 2025Article
- Heat Shock Protein and Disaggregase Influencing the Casein Structuralisation.International journal of molecular sciences · 2025Article
- CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation.Journal of inherited metabolic disease · 2025Review
- Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.Nature communications · 2025Article
- Biophysical and NMR analysis reveals binding affinity between HAX1 and CLPB proteins.Magnetic resonance letters · 2025Article
- Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.Apoptosis : an international journal on programmed cell death · 2025Article
- Design principles to tailor Hsp104 therapeutics.Cell reports · 2024Article
- Design principles to tailor Hsp104 therapeutics.bioRxiv : the preprint server for biology · 2024Article
- TheeLife · 2024Article
- CLPB disaggregase dysfunction impacts the functional integrity of the proteolytic SPY complex.The Journal of cell biology · 2024Article
- Dodecamer assembly of a metazoan AAAScience advances · 2023Article
- Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria.Nature communications · 2023Article
- Article
- Deciphering the mechanism and function of Hsp100 unfoldases from protein structure.Biochemical Society transactions · 2022Article
- AAA+ proteins: one motor, multiple ways to work.Biochemical Society transactions · 2022Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.