Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3
Open accessPublished version of a preprint
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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- Authors
- Cupo, R. R., Rizo, A. N., Braun, G. A., Tse, E., Chuang, E., Gupta, K., Southworth, D. R., & Shorter, J.
- Affiliations
- University of Pennsylvania (US)
- University of California, San Francisco (US)
- Corresponding author
- Southworth, Daniel R.
- Shorter, James
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 40
- Issue
- 13
- Pages
- 111408
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC9584538
- OpenAlex
- W4297373146
- Cited by
- 25
- References
- 6
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 3
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- G. Harold and Leila Y. Mathers Foundation
- National Institutes of Health (F31AG060672, R21AG061784, T32GM008275)
- NIGMS (R01GM099836, R01GM138690)
- Johnson Foundation
- Blavatnik Family Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- ClpB, AAA+ ATPase, protein disaggregation, mitochondrial intermembrane space, congenital neutropenia, nucleotide-binding domain, ankyrin repeat domain, disease inheritance, treatment options
- MeSH terms
- Adenosine Triphosphate, Heat-Shock Proteins, Humans, Models, Molecular, Nucleotides, Ankyrins, Protein Transport
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