The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling.
The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling.
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DOI：
10.1038/ncb3179
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发表时间：
2015-07
影响因子：
21.3
通讯作者：
Joglekar AP
中科院分区：
文献类型：
--
作者：
Aravamudhan P;Goldfarb AA;Joglekar AP
纺锤体组装检查点（SAC）是一种独特的信号传导机制，其响应于着丝粒与纺锤体微管的附着状态。SAC信号被未附着的动粒激活，并且在这些动粒形成端对微管附着后被沉默。虽然SAC信号的生化级联反应已经被很好地理解，但是如何将其破坏仍然是未知的。在这里，我们表明，在芽殖酵母中，端微管附着的动粒物理分离的Mps1激酶，这可能会结合到Ndc80的钙调蛋白同源结构域，从Mps1，Spc105（KNL1直系同源物）的动粒底物。这种附着介导的分离破坏了Spc105的磷酸化，并使SAC沉默。此外，Dam1复合物可以作为屏障，保护Spc105免受Mps1的侵害。总之，这些数据表明，着丝粒的蛋白质结构编码一个机械开关。微管与动粒的末端连接关闭了这个开关，使SAC沉默。
The Spindle Assembly Checkpoint (SAC) is a unique signaling mechanism that responds to the state of attachment of the kinetochore to spindle microtubules. SAC signaling is activated by unattached kinetochores, and it is silenced after these kinetochores form end-on microtubule attachments. Although the biochemical cascade of SAC signaling is well-understood, how kinetochore-microtubule attachment disrupts it remained unknown. Here we show that, in budding yeast, end-on microtubule attachment to the kinetochore physically separates the Mps1 kinase, which likely binds to the Calponin homology domain of Ndc80, from the kinetochore substrate of Mps1, Spc105 (KNL1 orthologue). This attachment-mediated separation disrupts the phosphorylation of Spc105, and enables SAC silencing. Additionally, the Dam1 complex may act as a barrier that shields Spc105 from Mps1. Together these data suggest that the protein architecture of the kinetochore encodes a mechanical switch. End-on microtubule attachment to the kinetochore turns this switch off to silence the SAC.