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Systemwide disassembly and assembly of SCF ubiquitin ligase complexes
Cell ( IF 45.5 ) Pub Date : 2023-04-06 , DOI: 10.1016/j.cell.2023.02.035
Kheewoong Baek 1 , Daniel C Scott 2 , Lukas T Henneberg 1 , Moeko T King 2 , Matthias Mann 3 , Brenda A Schulman 4
Affiliation  

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.



中文翻译:


SCF 泛素连接酶复合物的全系统拆卸和组装



细胞通过重塑多蛋白复合物的库存来响应环境信号。 SCF(SKP1-CUL1-F 盒蛋白)泛素连接酶复合物的细胞库可介导大量蛋白质降解,需要 CAND1 将限制性 CUL1 亚基分布在约 70 种不同 F 盒蛋白家族中。然而,单个因子如何协调组装众多不同的多蛋白复合物仍然未知。我们获得了 CAND1 结合的 SCF 复合物在多种状态下的冷冻电镜结构以及对结构、生物化学和细胞测定的相关突变效应。数据表明,CAND1 扣住非活性 SCF 的闲置催化域,滚动、变构晃动并破坏 SCF 的稳定性。新的 SCF 生产以相反的方式进行,通过 SKP1-F 盒变构破坏 CAND1 的稳定性。 CAND1-SCF 构象系综从非活性复合物中回收 CUL1,为 E3 激活的 SCF 部分的混合和匹配提供燃料,以响应底物的可用性。我们的数据揭示了 E3 连接酶主要家族的生物发生,以及全系统多蛋白复合物组装的分子基础。

更新日期:2023-04-06
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