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-Structure paper
タイトル | Dodecamer assembly of a metazoan AAA chaperone couples substrate extraction to refolding. |
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ジャーナル・号・ページ | Sci Adv, Vol. 9, Issue 19, Page eadf5336, Year 2023 |
掲載日 | 2023年5月10日 |
著者 | Arpit Gupta / Alfred M Lentzsch / Alex Siegel / Zanlin Yu / Un Seng Chio / Yifan Cheng / Shu-Ou Shan / |
PubMed 要旨 | Ring-forming AAA chaperones solubilize protein aggregates and protect organisms from proteostatic stress. In metazoans, the AAA chaperone Skd3 in the mitochondrial intermembrane space (IMS) is ...Ring-forming AAA chaperones solubilize protein aggregates and protect organisms from proteostatic stress. In metazoans, the AAA chaperone Skd3 in the mitochondrial intermembrane space (IMS) is critical for human health and efficiently refolds aggregated proteins, but its underlying mechanism is poorly understood. Here, we show that Skd3 harbors both disaggregase and protein refolding activities enabled by distinct assembly states. High-resolution structures of Skd3 hexamers in distinct conformations capture ratchet-like motions that mediate substrate extraction. Unlike previously described disaggregases, Skd3 hexamers further assemble into dodecameric cages in which solubilized substrate proteins can attain near-native states. Skd3 mutants defective in dodecamer assembly retain disaggregase activity but are impaired in client refolding, linking the disaggregase and refolding activities to the hexameric and dodecameric states of Skd3, respectively. We suggest that Skd3 is a combined disaggregase and foldase, and this property is particularly suited to meet the complex proteostatic demands in the mitochondrial IMS. |
リンク | Sci Adv / PubMed:37163603 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.76 - 6.8 Å |
構造データ | EMDB-26722, PDB-7us2: EMDB-26725: PARL-cleaved Skd3 (human ClpB) E455Q Nucleotide Binding Domain hexamer bound to ATPgammaS, open conformation EMDB-26726: PARL-cleaved Skd3 (human ClpB) E455Q Nucleotide Binding Domain hexamer bound to ATPgammaS, closed conformation EMDB-26728: PARL-cleaved Skd3 (human ClpB) E455Q dodecamer bound to ATPgammaS |
化合物 | ChemComp-AGS: ChemComp-MG: |
由来 |
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キーワード | CHAPERONE / AAA+ ATPase / Mitochondria / Protein Folding |