Structural and mechanistic insights into the CAND1-mediated SCF substrate receptor exchange.

Autor:	Shaaban M; The Visual Biochemistry Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK., Clapperton JA; The Visual Biochemistry Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK., Ding S; The Visual Biochemistry Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK., Kunzelmann S; Structural Biology Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK., Mäeots ME; The Visual Biochemistry Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK., Maslen SL; Proteomics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK., Skehel JM; Proteomics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK., Enchev RI; The Visual Biochemistry Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK. Electronic address: radoslav.enchev@crick.ac.uk.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2023 Jul 06; Vol. 83 (13), pp. 2332-2346.e8. Date of Electronic Publication: 2023 Jun 19.
DOI:	10.1016/j.molcel.2023.05.034
Abstrakt:	Modular SCF (SKP1-CUL1-Fbox) ubiquitin E3 ligases orchestrate multiple cellular pathways in eukaryotes. Their variable SKP1-Fbox substrate receptor (SR) modules enable regulated substrate recruitment and subsequent proteasomal degradation. CAND proteins are essential for the efficient and timely exchange of SRs. To gain structural understanding of the underlying molecular mechanism, we reconstituted a human CAND1-driven exchange reaction of substrate-bound SCF alongside its co-E3 ligase DCNL1 and visualized it by cryo-EM. We describe high-resolution structural intermediates, including a ternary CAND1-SCF complex, as well as conformational and compositional intermediates representing SR- or CAND1-dissociation. We describe in molecular detail how CAND1-induced conformational changes in CUL1/RBX1 provide an optimized DCNL1-binding site and reveal an unexpected dual role for DCNL1 in CAND1-SCF dynamics. Moreover, a partially dissociated CAND1-SCF conformation accommodates cullin neddylation, leading to CAND1 displacement. Our structural findings, together with functional biochemical assays, help formulate a detailed model for CAND-SCF regulation. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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