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Title | Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3. |
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Journal, issue, pages | Cell Rep, Vol. 40, Issue 13, Page 111408, Year 2022 |
Publish date | Sep 27, 2022 |
Authors | Ryan R Cupo / Alexandrea N Rizo / Gabriel A Braun / Eric Tse / Edward Chuang / Kushol Gupta / Daniel R Southworth / James Shorter / |
PubMed 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 ...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. |
External links | Cell Rep / PubMed:36170828 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.9 - 2.96 Å |
Structure data | EMDB-26121, PDB-7ttr: EMDB-26122, PDB-7tts: |
Chemicals | ChemComp-ADP: ChemComp-MG: ChemComp-AGS: |
Source |
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Keywords | CHAPERONE / cryoEM / AAA+ |