Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression
Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression
复制标题
DOI：
10.1242/jcs.122481
复制
发表时间：
2013-03-01
影响因子：
4
通讯作者：
Nilsson, Jakob
中科院分区：
文献类型：
--
作者：
Kruse, Thomas;Zhang, Gang;Nilsson, Jakob
BubR1是纺锤体组装检查点的中心组成部分，它可以抑制进入后期，以响应不正确的动粒-微管作用。此外，BubR1还通过对抗Aurora B激酶来帮助稳定动粒-微管相互作用，但其背后的机制尚不清楚。在这里，我们证明了BubR1通过一个保守的基序直接与蛋白磷酸酶2A(PP2A)调节亚基的B56家族结合，该基序被细胞周期蛋白依赖激酶1(CDK1)和Polo样激酶1(Plk1)磷酸化。B56结合需要丝氨酸670CDK1磷酸化位点周围两个高度保守的疏水残基。这些残基的突变阻止了适当中期平板的建立，并延迟了细胞的有丝分裂。此外，我们证明了丝氨酸670和676的磷酸化刺激B56与BubR1的结合，而BubR1靶向B56与动素中心的池。我们的数据表明，BubR1通过招募B56-PP2A磷酸酶复合体来抵消不正确连接的动粒上的Aurora B激酶活性。
BubR1 is a central component of the spindle assembly checkpoint that inhibits progression into anaphase in response to improper kinetochore-microtubule interactions. In addition, BubR1 also helps stabilize kinetochore-microtubule interactions by counteracting the Aurora B kinase but the mechanism behind this is not clear. Here we show that BubR1 directly binds to the B56 family of protein phosphatase 2A (PP2A) regulatory subunits through a conserved motif that is phosphorylated by cyclin-dependent kinase 1 (Cdk1) and polo-like kinase 1 (Plk1). Two highly conserved hydrophobic residues surrounding the serine 670 Cdk1 phosphorylation site are required for B56 binding. Mutation of these residues prevents the establishment of a proper metaphase plate and delays cells in mitosis. Furthermore, we show that phosphorylation of serines 670 and 676 stimulates the binding of B56 to BubR1 and that BubR1 targets a pool of B56 to kinetochores. Our data suggest that BubR1 counteracts Aurora B kinase activity at improperly attached kinetochores by recruiting B56-PP2A phosphatase complexes.