The Dimeric Architecture of Checkpoint Kinases Mec1ATR and Tel1ATM Reveal a Common Structural Organization.
The Dimeric Architecture of Checkpoint Kinases Mec1ATR and Tel1ATM Reveal a Common Structural Organization.
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DOI：
10.1074/jbc.m115.708263
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发表时间：
2016-06-24
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Sawicka M;Wanrooij PH;Darbari VC;Tannous E;Hailemariam S;Bose D;Makarova AV;Burgers PM;Zhang X
磷脂酰肌醇3-激酶相关蛋白激酶是控制广泛细胞事件的关键调节因子。酵母的Tel1和Mec1·Ddc2复合体（ATM和ATR-ATRIP）在DNA复制、DNA损伤信号传导和修复中起着关键作用。在这里，我们首次使用单粒子电子显微镜对Mec1·Ddc2和Tel1二聚体的结构进行了分析。这两种激酶通过n端HEAT（以亨廷顿蛋白、延伸因子3、蛋白磷酸酶2A和酵母激酶TOR1命名）重复序列显示出一个头对头二聚体，具有一个主要的二聚体界面。它们的二聚体界面明显不同于mTOR复合物1二聚体的界面，后者通过两个空间分离的界面进行寡聚。我们还观察到Mec1和Tel1激酶结构域的不同结构组织。Mec1·Ddc2二聚体中的激酶结构域彼此靠近。然而，在Tel1二聚体中，它们是完全分离的，提供了潜在的底物进入这种激酶的途径，即使是在它的二聚体形式中。
The phosphatidylinositol 3-kinase-related protein kinases are key regulators controlling a wide range of cellular events. The yeast Tel1 and Mec1·Ddc2 complex (ATM and ATR-ATRIP in humans) play pivotal roles in DNA replication, DNA damage signaling, and repair. Here, we present the first structural insight for dimers of Mec1·Ddc2 and Tel1 using single-particle electron microscopy. Both kinases reveal a head to head dimer with one major dimeric interface through the N-terminal HEAT (named after Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR1) repeat. Their dimeric interface is significantly distinct from the interface of mTOR complex 1 dimer, which oligomerizes through two spatially separate interfaces. We also observe different structural organizations of kinase domains of Mec1 and Tel1. The kinase domains in the Mec1·Ddc2 dimer are located in close proximity to each other. However, in the Tel1 dimer they are fully separated, providing potential access of substrates to this kinase, even in its dimeric form.