8OR4

Partially dissociated CAND1-CUL1-RBX1-SKP1-SKP2-CKS1-CDK2

Summary for 8OR4

• Entry DOI: 10.2210/pdb8or4/pdb
• Related: 8OR0 8OR2 8OR3
• EMDB information: 17117
• Descriptor: Cullin-1, E3 ubiquitin-protein ligase RBX1, Cullin-associated NEDD8-dissociated protein 1, ... (7 entities in total)
• Functional Keywords: cand1, substrate receptor exchange factor, cullin-ring ligase, crl, scf, ligase, neddylation, dcnl1 co-e3, ubiquitin signaling
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 353264.75

Authors

Shaaban, M.,Clapperton, J.A.,Ding, S.,Maeots, M.E.,Enchev, R.I. (deposition date: 2023-04-13, release date: 2023-06-28, Last modification date: 2024-07-24)

Primary citation

Shaaban, M.,Clapperton, J.A.,Ding, S.,Kunzelmann, S.,Maeots, M.E.,Maslen, S.L.,Skehel, J.M.,Enchev, R.I.
Structural and mechanistic insights into the CAND1-mediated SCF substrate receptor exchange.
Mol.Cell, 83:2332-, 2023

PubMed Abstract: 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.

PubMed: 37339624
DOI: 10.1016/j.molcel.2023.05.034

Experimental method

ELECTRON MICROSCOPY (3.8 Å)