Systemwide disassembly and assembly of SCF ubiquitin ligase complexes.

Autor:	Baek K; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried 82152, Germany., Scott DC; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Henneberg LT; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried 82152, Germany., King MT; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Mann M; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany., Schulman BA; Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried 82152, Germany; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: schulman@biochem.mpg.de.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2023 Apr 27; Vol. 186 (9), pp. 1895-1911.e21. Date of Electronic Publication: 2023 Apr 06.
DOI:	10.1016/j.cell.2023.02.035
Abstrakt:	Cells respond to environmental cues by remodeling their inventories of multiprotein complexes. Cellular repertoires of SCF (SKP1-CUL1-F box protein) ubiquitin ligase complexes, which mediate much protein degradation, require CAND1 to distribute the limiting CUL1 subunit across the family of ∼70 different F box proteins. Yet, how a single factor coordinately assembles numerous distinct multiprotein complexes remains unknown. We obtained cryo-EM structures of CAND1-bound SCF complexes in multiple states and correlated mutational effects on structures, biochemistry, and cellular assays. The data suggest that CAND1 clasps idling catalytic domains of an inactive SCF, rolls around, and allosterically rocks and destabilizes the SCF. New SCF production proceeds in reverse, through SKP1-F box allosterically destabilizing CAND1. The CAND1-SCF conformational ensemble recycles CUL1 from inactive complexes, fueling mixing and matching of SCF parts for E3 activation in response to substrate availability. Our data reveal biogenesis of a predominant family of E3 ligases, and the molecular basis for systemwide multiprotein complex assembly. Competing Interests: Declaration of interests B.A.S. is also Honorary Professor at Technical University of Munich and serves on Interline Therapeutics and BioTheryX SABs. B.A.S. and D.C.S. co-invented intellectual property licensed to CinSano. M.M. is also Professor at Novo Nordisk Foundation Center for Protein Research. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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