Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.
Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.
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DOI：
10.1016/j.str.2018.05.014
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发表时间：
2018-08-07
期刊：
影响因子：
--
通讯作者：
Sicheri F
中科院分区：
文献类型：
--
作者：
Xiong S;Lorenzen K;Couzens AL;Templeton CM;Rajendran D;Mao DYL;Juang YC;Chiovitti D;Kurinov I;Guettler S;Gingras AC;Sicheri F
人类NDR家族激酶控制细胞生长的各个方面，并通过磷酸化和与支架如MOB 1的结合来调节。在这里，我们报告了人NDR 1激酶结构域在其非磷酸化状态下的晶体结构，揭示了一个完全解析的长激活片段，该片段阻断底物结合并稳定螺旋αC的非生产性位置。与自身抑制功能一致，NDR 1激活片段内的突变显著增强体外激酶活性。有趣的是，NDR 1的催化活性进一步增强MOB 1结合，这表明通过调节激活片段和MOB 1结合的调节机制是不同的。最后，删除NDR 1的自抑制激活片段导致与上游Hippo途径组分和Furry支架的关联显著增加。这些发现为进一步研究NDR 1的细胞功能和机制提供了一个出发点。2.2 NDR 1的激活片段影响与MST 1/2的相互作用，Furry NDR家族激酶在调节细胞周期和从酵母到人的生长中起重要作用。为了了解NDR家族激酶是如何调节的，Xiong et al.确定人NDR 1激酶结构域在其非磷酸化失活状态下的晶体结构。
The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase domain in its non-phosphorylated state, revealing a fully resolved atypically long activation segment that blocks substrate binding and stabilizes a non-productive position of helix αC. Consistent with an auto-inhibitory function, mutations within the activation segment of NDR1 dramatically enhance in vitro kinase activity. Interestingly, NDR1 catalytic activity is further potentiated by MOB1 binding, suggesting that regulation through modulation of the activation segment and by MOB1 binding are mechanistically distinct. Lastly, deleting the auto-inhibitory activation segment of NDR1 causes a marked increase in the association with upstream Hippo pathway components and the Furry scaffold. These findings provide a point of departure for future efforts to explore the cellular functions and the mechanism of NDR1. 2.2 Å crystal structure of an inactive human NDR1 kinase domain is determined An atypically long activation segment auto-inhibits the NDR1 kinase domain MOB1 and the activation segment of NDR1 act through independent mechanisms The activation segment of NDR1 influences interaction with MST1/2 and Furry NDR family kinases play important roles in regulating cell cycle and growth from yeast to human. To understand how NDR family kinases are regulated, Xiong et al. determine the crystal structure of human NDR1 kinase domain in its non-phosphorylated inactive state.
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影响因子：
64.5
作者：
Dey, M;Cao, C;Dever, TE
通讯作者：
Dever, TE
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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