The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex.
The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex.
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DOI：
10.1038/s41467-023-37235-z
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发表时间：
2023-03-18
影响因子：
16.6
通讯作者：
Joglekar AP
中科院分区：
文献类型：
--
作者：
Chen C;Piano V;Alex A;Han SJY;Huis In 't Veld PJ;Roy B;Fergle D;Musacchio A;Joglekar AP
纺锤体装配检查点 (SAC) 通过生成称为有丝分裂检查点复合物 (MCC) 的效应分子，在细胞分裂过程中保护基因组。 MCC 包含两个子复合物：BUBR1:BUB3 和 CDC20:MAD2，CDC20:MAD2 的形成是 MCC 组装过程中的限速步骤。最近的研究表明，CDC20 与 SAC 蛋白 MAD1 和 BUB1 的协同结合显着加快了 CDC20:MAD2 的形成速度。然而，这种加速的分子基础尚不完全清楚。在这里，我们证明 MAD1 在 C 末端附近的保守铰链处的结构灵活性对于催化 MCC 组装至关重要。该 MAD1 铰链使 MAD1:MAD2 复合物在体内呈现折叠构象。重要的是，截断铰链会降低体外 MCC 组装率和体内 SAC 信号传导率。相反，保留铰链灵活性的突变保留了 SAC 信号传导，这表明铰链的结构灵活性，而不是特定的氨基酸序列，对 SAC 信号传导很重要。我们将这些观察结果总结为“编织模型”，解释了 MAD1:MAD2 的折叠构象如何促进 CDC20:MAD2 组装。有丝分裂检查点复合体的形成需要蛋白质 Bub1、Mad1、Cdc20 和 Mad2 之间复杂的空间协调。 Chen 等人表明，Mad1 的结构灵活性在实现这种协调方面发挥着至关重要的作用。
The spindle assembly checkpoint (SAC) safeguards the genome during cell division by generating an effector molecule known as the Mitotic Checkpoint Complex (MCC). The MCC comprises two subcomplexes: BUBR1:BUB3 and CDC20:MAD2, and the formation of CDC20:MAD2 is the rate-limiting step during MCC assembly. Recent studies show that the rate of CDC20:MAD2 formation is significantly accelerated by the cooperative binding of CDC20 to the SAC proteins MAD1 and BUB1. However, the molecular basis for this acceleration is not fully understood. Here, we demonstrate that the structural flexibility of MAD1 at a conserved hinge near the C-terminus is essential for catalytic MCC assembly. This MAD1 hinge enables the MAD1:MAD2 complex to assume a folded conformation in vivo. Importantly, truncating the hinge reduces the rate of MCC assembly in vitro and SAC signaling in vivo. Conversely, mutations that preserve hinge flexibility retain SAC signaling, indicating that the structural flexibility of the hinge, rather than a specific amino acid sequence, is important for SAC signaling. We summarize these observations as the ‘knitting model’ that explains how the folded conformation of MAD1:MAD2 promotes CDC20:MAD2 assembly. The formation of the mitotic checkpoint complex requires an intricate spatial coordination amongst the proteins Bub1, Mad1, Cdc20, and Mad2. Chen et al show that a structural flexibility in Mad1 plays an essential role in achieving this coordination.
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