7US2

PARL-cleaved Skd3 (human ClpB) E455Q Nucleotide Binding Domain hexamer bound to ATPgammaS, open conformation

Summary for 7US2

• Entry DOI: 10.2210/pdb7us2/pdb
• EMDB information: 26722 26725 26726 26728
• Descriptor: Caseinolytic peptidase B protein homolog, Substrate, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, ... (4 entities in total)
• Functional Keywords: aaa+ atpase, chaperone, mitochondria, protein folding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 399972.09

Authors

Gupta, A.,Lentzsch, A.M.,Siegel, A.S.,Yu, Z.,Lu, C.,Chio, U.S.,Cheng, Y.,Shan, S.-o. (deposition date: 2022-04-22, release date: 2023-04-26, Last modification date: 2023-11-08)

Primary citation

Gupta, A.,Lentzsch, A.M.,Siegel, A.,Yu, Z.,Chio, U.S.,Cheng, Y.,Shan, S.O.
Dodecamer assembly of a metazoan AAA + chaperone couples substrate extraction to refolding.
Sci Adv, 9:eadf5336-eadf5336, 2023

PubMed Abstract: 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.

PubMed: 37163603
DOI: 10.1126/sciadv.adf5336

Experimental method

ELECTRON MICROSCOPY (2.76 Å)