小柯机器人

瑞士日内瓦大学Andreas Boland团队揭示人类分离酶受保全素和CDK1-cyclin B1调节的结构基础。相关论文于2021年7月21日在线发表在《自然》杂志上。

研究人员使用冷冻电镜确定了人类分离酶与保全素或CDK1-cyclin B1-CKS1形成复合物的结构。在这两种复合物中，分离酶都被假底物模体所抑制，这些模体在催化部位和附近的对接部位阻止底物的结合。如同在线虫和酵母中一样，人类保全素含有自己的假底物模体。相比之下，CDK1-cyclin B1通过部署来自分离酶本身的内在无序环的假底物模体来抑制分离酶。一个自体抑制环被CDK1-cyclin B1定向，从而阻断分离酶和CDK1的催化部位。

另一个自动抑制环阻止底物停靠在分离酶催化部位附近的裂缝中。第三个分离酶环包含一个磷酸丝氨酸，它通过与细胞周期蛋白B1中保守的磷酸盐结合口袋结合来促进复合物的组装。这项研究揭示了保全素和CDK1-cyclin B1结合和抑制分离酶的各种机制，为染色体分离的有力控制提供了分子基础。

据介绍，在有丝分裂早期，复制的染色体被环形的黏连蛋白复合物固定在一起。染色体的分离是由分离酶触发的，这是是一种大型的半胱氨酸内肽酶，它能切割粘连蛋白亚单位SCC1（也被称为RAD21）。分离酶通过其抑制因子保全素和cyclin B6的降解而被激活，但分离酶的分子调节机制并不清楚。

附：英文原文

Title: Structural basis of human separase regulation by securin and CDK1–cyclin B1

Author: Jun Yu, Pierre Raia, Chloe M. Ghent, Tobias Raisch, Yashar Sadian, Simone Cavadini, Pramod M. Sabale, David Barford, Stefan Raunser, David O. Morgan, Andreas Boland

Issue&Volume: 2021-07-21

Abstract: In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex1. Separation of chromosomes during anaphase is triggered by separase—a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD212,3,4). Separase is activated by degradation of its inhibitors, securin5 and cyclin B6, but the molecular mechanisms of separase regulation are not clear. Here we used cryogenic electron microscopy to determine the structures of human separase in complex with either securin or CDK1–cyclin B1–CKS1. In both complexes, separase is inhibited by pseudosubstrate motifs that block substrate binding at the catalytic site and at nearby docking sites. As in Caenorhabditis elegans7 and yeast8, human securin contains its own pseudosubstrate motifs. By contrast, CDK1–cyclin B1 inhibits separase by deploying pseudosubstrate motifs from intrinsically disordered loops in separase itself. One autoinhibitory loop is oriented by CDK1–cyclin B1 to block the catalytic sites of both separase and CDK19,10. Another autoinhibitory loop blocks substrate docking in a cleft adjacent to the separase catalytic site. A third separase loop contains a phosphoserine6 that promotes complex assembly by binding to a conserved phosphate-binding pocket in cyclin B1. Our study reveals the diverse array of mechanisms by which securin and CDK1–cyclin B1 bind and inhibit separase, providing the molecular basis for the robust control of chromosome segregation.

DOI: 10.1038/s41586-021-03764-0

Source: https://www.nature.com/articles/s41586-021-03764-0

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