Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1.
Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1.
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DOI：
10.1016/j.cub.2014.05.002
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发表时间：
2014-06-16
期刊：
影响因子：
9.2
通讯作者：
Pryciak, Peter M.
中科院分区：
文献类型：
--
作者：
Pope, Patricia A.;Bhaduri, Samyabrata;Pryciak, Peter M.
真核细胞的分裂通常受细胞外信号的调控。在萌芽酵母中，交配信息素发出的信号阻止细胞周期进入G1期。这种停滞需要FAR1蛋白，它被认为通过发挥CDK抑制物(CKI)的作用来对抗G1/S的转变，尽管其机制仍未解决。最近的研究发现，G1/S细胞周期蛋白(Cln1和Cln2)通过特定的对接基序识别CDK底物，促进底物在体内的磷酸化。在这里，我们证明了这些对接相互作用被信息素信号抑制，并且这种抑制需要FAR1。此外，不能抑制对接的Far1突变体在细胞周期停滞时是有缺陷的。与这种阻止功能一致，在体内，FAR1在与G1/S周期蛋白的结合方面优于底物，并且在信息素可以实施G1抑制的预承诺期，它的存在远远超过G1/S周期蛋白。最后，对需要和不需要对接的底物的比较表明，Far1作为一种多模式抑制剂，对抗Cln1/2-CDK复合体的激酶活性和底物识别。我们的发现揭示了CDK受外部信号调控的一种新机制，并为了解Far1的功能提供了一个修正的观点，在这个模型系统中。
Eukaryotic cell division is often regulated by extracellular signals. In budding yeast, signaling from mating pheromones arrests the cell cycle in G1 phase. This arrest requires the protein Far1, which is thought to antagonize the G1/S transition by acting as a Cdk inhibitor (CKI), although the mechanisms remain unresolved. Recent studies found that G1/S cyclins (Cln1 and Cln2) recognize Cdk substrates via specific docking motifs, which promote substrate phosphorylation in vivo. Here, we show that these docking interactions are inhibited by pheromone signaling, and that this inhibition requires Far1. Moreover, Far1 mutants that cannot inhibit docking are defective at cell cycle arrest. Consistent with this arrest function, Far1 outcompetes substrates for association with G1/S cyclins in vivo, and it is present in large excess over G1/S cyclins during the pre-commitment period where pheromone can impose G1 arrest. Finally, a comparison of substrates that do and do not require docking suggests that Far1 acts as a multi-mode inhibitor that antagonizes both kinase activity and substrate recognition by Cln1/2-Cdk complexes. Our findings uncover a novel mechanism of Cdk regulation by external signals, and shed new light on Far1 function to provide a revised view of cell cycle arrest in this model system.
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