How the kinetochore switches off the spindle assembly checkpoint.
How the kinetochore switches off the spindle assembly checkpoint.
复制标题
动粒如何关闭主轴组件检查点。
DOI：
10.1080/15384101.2015.1112695
复制
发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Aravamudhan,Pavithra
中科院分区：
文献类型：
--
作者：
Joglekar,AjitP;Aravamudhan,Pavithra
The eukaryotic kinetochore senses whether or not it is attached to spindle microtubules. If unattached, it activates the signaling cascade of the Spindle Assembly Checkpoint (SAC) and delays cell division. The biochemistry of SAC signaling is well-understood. However, the molecular mechanism that couples SAC activation and inactivation to the attachment state of the kinetochore has been an enduring question in cell biology. Three recent studies address this question, but propose 2 different mechanisms, one mechanical in nature and the other based on biochemical competition. 1-3 Here we highlight key results that led us to the ‘mechanical switch’model, and propose that the SAC is silenced by a hybrid mechanism that uses biochemical competition as well as a mechanical switch. An unattached kinetochore initiates SAC signaling by enabling the phosphorylation of the kinetochore protein Spc105/KNL-1 by Mps1 kinase. This allows the kinetochore to recruit SAC proteins and generate the ‘wait-anaphase’signal. After the kinetochore forms end-on microtubule attachment, it sheds SAC proteins and stops signaling. Two types of mechanisms can explain the attachment-induced removal of SAC proteins from the kinetochore. Microtubule attachment may interfere with the binding of one or more SAC proteins either by creating steric hindrance or by competing for a common binding site in the kinetochore. Alternatively, it may disrupt protein interactions mechanically, by changing protein organization in the kinetochore. 4To understand the mechanism of SAC silencing, we investigated the relatively simple budding yeast kinetochore that has a well-defined protein organization. 5 We found that the yeast kinetochore encodes a microtubule-operated mechanical switch to control the SAC. In a mechanical switch, the closing of 2 terminals allows electricity to flow, while opening them stops this flow. In a similar manner, the Calponin-Homology domains of the Ndc80 complex and the phosphodomain of Spc105 operate as 2 protein terminals in the yeast kinetochore. They come together when the kinetochore is unattached, allowing Mps1 bound to the Calponin-Homology domains to phosphorylate Spc105 and activate the SAC (Fig. 1, top). Because these domains contain microtubule-binding sites, end-on microtubule attachment separates them by~ 30 nm (Fig. 1, bottom). Now, Mps1 can no longer phosphorylate Spc105, and the SAC is inactivated. Thus, the nanoscale protein organization of the
