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-Structure paper
タイトル | Structural and mechanistic insights into the CAND1-mediated SCF substrate receptor exchange. |
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ジャーナル・号・ページ | Mol Cell, Vol. 83, Issue 13, Page 2332-22346.e8, Year 2023 |
掲載日 | 2023年7月6日 |
著者 | Mohammed Shaaban / Julie A Clapperton / Shan Ding / Simone Kunzelmann / Märt-Erik Mäeots / Sarah L Maslen / J Mark Skehel / Radoslav I Enchev / |
PubMed 要旨 | 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 ...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. |
リンク | Mol Cell / PubMed:37339624 |
手法 | EM (単粒子) |
解像度 | 2.9 - 8.3 Å |
構造データ | EMDB-17114, PDB-8or0: EMDB-17115, PDB-8or2: EMDB-17116, PDB-8or3: EMDB-17117, PDB-8or4: EMDB-17124: CAND1-CUL1-RBX1 |
化合物 | ChemComp-ZN: |
由来 |
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キーワード | LIGASE / CAND1 / substrate receptor exchange factor / cullin-RING ligase / CRL / SCF / neddylation / DCNL1 co-E3 / ubiquitin signaling |