CDC20 assists its catalytic incorporation in the mitotic checkpoint complex
CDC20 assists its catalytic incorporation in the mitotic checkpoint complex
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DOI：
10.1126/science.abc1152
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发表时间：
2021-01-01
期刊：
影响因子：
56.9
通讯作者：
Musacchio, Andrea
中科院分区：
文献类型：
--
作者：
Piano, Valentina;Alex, Amal;Musacchio, Andrea
HORMA结构域蛋白的开放（O）和闭合（C）拓扑分别与基本细胞途径的非活性和活性状态相关。HORMA蛋白O-MAD 2在结合CDC 20后转化为C-MAD 2。这是有丝分裂检查点复合物（MCC）组装的速率限制，MCC是有丝分裂保真度所需的检查点效应物。在着丝粒组装的催化剂通过一种知之甚少的机制加速MAD 2：CDC 20的缔合。使用重组SAC系统，我们发现，CDC 20是一个不可渗透的基板，其访问MAD 2需要同时对接在催化复合物的几个位点上。我们的分析表明，检查点催化剂是基板辅助和促进MCC组装通过空间和时间协调的构象变化在MAD 2和CDC 20。这可以定义其他HORMA控制系统的范例。
Open (O) and closed (C) topologies of HORMA-domain proteins are respectively associated with inactive and active states of fundamental cellular pathways. The HORMA protein O-MAD2 converts to C-MAD2 upon binding CDC20. This is rate limiting for assembly of the mitotic checkpoint complex (MCC), the effector of a checkpoint required for mitotic fidelity. A catalyst assembled at kinetochores accelerates MAD2:CDC20 association through a poorly understood mechanism. Using a reconstituted SAC system, we discovered that CDC20 is an impervious substrate for which access to MAD2 requires simultaneous docking on several sites of the catalytic complex. Our analysis indicates that the checkpoint catalyst is substrate assisted and promotes MCC assembly through spatially and temporally coordinated conformational changes in both MAD2 and CDC20. This may define a paradigm for other HORMA-controlled systems.