PDF(Pubmed)
Abstract：
The ankyrin (ANK) SOCS box (ASB) family, encompassing ASB1-18, is the largest group of substrate receptors of cullin 5 Ring E3 ubiquitin ligase. Nonetheless, the mechanism of substrate recognition by ASB family proteins has remained largely elusive. Here we present the crystal structure of ASB7-Elongin B-Elongin C ternary complex bound to a conserved helical degron. ASB7 employs its ANK3-6 to form an extended groove, effectively interacting with the internal α-helix-degron through a network of side-chain-mediated electrostatic and hydrophobic interactions. Our structural findings, combined with biochemical and cellular analyses, identify the key residues of the degron motif and ASB7 required for their recognition. This will facilitate the identification of additional physiological substrates of ASB7 by providing a defined degron motif for screening. Furthermore, the structural insights provide a basis for the rational design of compounds that can specifically target ASB7 by disrupting its interaction with its cognate degron.
摘要：
ankyrin（ANK）SOCS箱（ASB）系列，包含ASB1-18，是cullin5环E3泛素连接酶的最大底物受体组。尽管如此，ASB家族蛋白的底物识别机制在很大程度上仍然难以捉摸。在这里，我们介绍了与保守的螺旋degron结合的ASB7-ElonginB-ElonginC三元复合物的晶体结构。ASB7采用其ANK3-6形成一个延伸的凹槽，通过侧链介导的静电和疏水相互作用网络与内部α-螺旋-degron有效相互作用。我们的结构发现，结合生化和细胞分析，鉴定识别所需的degron基序和ASB7的关键残基。通过提供用于筛选的确定的degron基序，这将有助于鉴定ASB7的其他生理底物。此外，结构见解为合理设计可以通过破坏ASB7与其同源degron的相互作用来特异性靶向ASB7的化合物提供了基础。
