Year: 2024
Type: article
Abstract: The Cdc48 AAA+ ATPase is an abundant and essential enzyme that unfolds substrates in multiple protein quality control pathways. The enzyme includes two conserved AAA+ ATPase cassettes, D1 and D2, that assemble as hexameric rings with D1 stacked above D2. Here, we report an ensemble of structures of Cdc48 affinity purified from lysate in complex with the adaptor Shp1 in the act of unfolding substrate. Our analysis reveals a continuum of structural snapshots that spans the entire translocation cycle. These data reveal new elements of Shp1-Cdc48 binding and support a “hand-over-hand” mechanism in which the sequential movement of individual subunits is closely coordinated. D1 hydrolyzes ATP and disengages from substrate prior to D2, while D2 rebinds ATP and re-engages with substrate prior to D1, thereby explaining the dominant role played by D2 in substrate translocation/unfolding.
Source: Nature Communications
Authors: Ian Cooney, Heidi L. Schubert, Karina Cedeno, Olivia N. Fisher, Richard Carson, John C. Price, Christopher P. Hill, Peter S. Shen
Institutions: University of Utah, Brigham Young University
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Health and Human Services, Brigham Young University, University of Utah, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Awards: G1928141884, Biochemical Consequences of Regiospecific Metabolic Bias in the Brain, G2473428791, G4195978581, G5520316217, CHEETAH Center for the Structural Biology of HIV Infection, Restriction, and Viral Dynamics, G5950577451, Resolving the mechanism of cofactor and substrate interactions with Cdc48, G6406201321, G7024251865, G7084652348, G7357719943, G9000086088, ESCRT and MIT Complexes in Cytokinesis, Visualizing the Mechanisms of Protein Quality Control
OpenAlex ID: W4401987352