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Structural basis of the phosphorylation-independent recognition of cyclin D1 by the SCFFBXO31 ubiquitin ligase
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2018-01-09 00:00:00 , DOI: 10.1073/pnas.1708677115
Yunfeng Li 1 , Kai Jin 1 , Eric Bunker 2 , Xiaojuan Zhang 2 , Xuemei Luo 3 , Xuedong Liu 2 , Bing Hao 4
Affiliation  

Ubiquitin-dependent proteolysis of cyclin D1 is associated with normal and tumor cell proliferation and survival. The SCFFBXO31 (Skp1–Cul1–Rbx1–FBXO31) ubiquitin ligase complex mediates genotoxic stress-induced cyclin D1 degradation. Previous studies have suggested that cyclin D1 levels are maintained at steady state by phosphorylation-dependent nuclear export and subsequent proteolysis in the cytoplasm. Here we present the crystal structures of the Skp1–FBXO31 complex alone and bound to a phosphorylated cyclin D1 C-terminal peptide. FBXO31 possesses a unique substrate-binding domain consisting of two β-barrel motifs, whereas cyclin D1 binds to FBXO31 by tucking its free C-terminal carboxylate tail into an open cavity of the C-terminal FBXO31 β-barrel. Biophysical and functional studies demonstrate that SCFFBXO31 is capable of recruiting and ubiquitinating cyclin D1 in a phosphorylation-independent manner. Our findings provide a conceptual framework for understanding the substrate specificity of the F-box protein FBXO31 and the mechanism of FBXO31-regulated cyclin D1 protein turnover.

中文翻译:

SCFFBXO31泛素连接酶对细胞周期蛋白D1的磷酸化非依赖性识别的结构基础

细胞周期蛋白 D1 的泛素依赖性蛋白水解与正常和肿瘤细胞增殖和存活有关。所述SCF FBXO31(SKP1-CUL1-Rbx1成为-FBXO31)泛素连接酶复合物介导的基因毒性应激诱导的细胞周期蛋白D1的降解。以前的研究表明,细胞周期蛋白 D1 水平通过磷酸化依赖性核输出和随后的细胞质蛋白水解维持在稳定状态。在这里,我们单独展示了 Skp1-FBXO31 复合物的晶体结构,并与磷酸化的细胞周期蛋白 D1 C 末端肽结合。FBXO31 拥有一个独特的底物结合结构域,由两个 β-桶基序组成,而细胞周期蛋白 D1 通过将其游离的 C 末端羧酸盐尾塞入 C 末端 FBXO31 β-桶的开放腔中来与 FBXO31 结合。生物物理和功能研究表明,SCFFBXO31能够以不依赖磷酸化的方式募集和泛素化 cyclin D1。我们的研究结果为理解 F-box 蛋白 FBXO31 的底物特异性和 FBXO31 调节的细胞周期蛋白 D1 蛋白转换的机制提供了一个概念框架。
更新日期:2018-01-10
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