Structural insights into regulatory mechanisms of MO25-mediated kinase activation
Structural insights into regulatory mechanisms of MO25-mediated kinase activation
复制标题
MO25 介导的激酶激活调节机制的结构见解
DOI：
10.1016/j.jsb.2014.04.005
复制
发表时间：
2014-05-01
影响因子：
3
通讯作者：
Zhou, Zhaocai
中科院分区：
文献类型：
--
作者：
Hao, Qian;Feng, Miao;Zhou, Zhaocai
肿瘤抑制激酶LKB 1和生殖中心激酶（GCK）是各种细胞功能的关键调节因子。衔接分子MO 25不仅通过假激酶STRAD募集和激活LKBI，而且还可以直接激活GCK如MST 3、MST 4、STK 25、OSRI和SPAK。最近已经在小鼠中研究了在病理环境中靶向M0 25。然而，MO 25介导的激酶激活的调节机制尚未完全了解。在这里，我们对MO 25相关激酶的结构研究表明，MO 25通过统一的结构机制结合并激活GCK激酶或假激酶，其特征在于由MO 25稳定的α C螺旋和A环的活性构象。与通过MO 25结合直接激活的GCK相比，LKB 1的激活已经进化出了额外的一层调节机制，即，M0 25“激活”假激酶STRAD，其进而激活LKBI。重要的是，在这项工作中确定的MO 25 α-STK 25和MO 25 α-MST 3的结构分别代表了MO 25介导的激酶激活过程中的过渡/中间状态和完全激活状态。(C)2014爱思唯尔公司All rights reserved.
The tumor suppressor kinase LKB1 and germinal center kinases (GCKs) are key regulators of various cellular functions. The adaptor molecule MO25 not only recruits and activates LKBI through the pseudokinase STRAD, but also may directly activate GCKs like MST3, MST4, STK25, OSRI and SPAK. Targeting MO25 in a pathological setting has been recently studied in mouse. Yet the regulatory mechanism of MO25-mediated kinase activation is not fully understood. Here, our structural studies of MO25-related kinases reveal that MO25 binds to and activates GCK kinases or pseudokinase through a unified structural mechanism, featuring an active conformation of the alpha C helix and A-loop stabilized by MO25. Compared to GCKs that are directly activated by MO25-binding, activation of LKB1 has evolved additional layer of regulatory machinery, i.e., MO25 "activates" the pseudokinase STRAD, which in turn activates LKBI. Importantly, the structures of MO25 alpha-STK25 and MO25 alpha-MST3 determined in this work represent a transition/intermediate state and a fully activated state, respectively during the MO25-mediated kinase activating process. (C) 2014 Elsevier Inc. All rights reserved.