Structural basis for autoinhibition and its relief of MOB1 in the Hippo pathway.
Structural basis for autoinhibition and its relief of MOB1 in the Hippo pathway.
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DOI：
10.1038/srep28488
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发表时间：
2016-06-23
影响因子：
4.6
通讯作者：
Hakoshima T
中科院分区：
文献类型：
--
作者：
Kim SY;Tachioka Y;Mori T;Hakoshima T
MOB1 蛋白是 Hippo 通路中大肿瘤抑制因子 1/2 (LATS1/2) 激酶的关键调节因子。 MOB1 以自抑制形式存在，并由 MST1/2 介导的磷酸化激活，但由于缺乏自抑制 MOB1 结构，负责自抑制和激活的精确机制尚不清楚。在这里，我们报告了自抑制形式的全长 MOB1B 的晶体结构以及 MOB1B 核心结构域和 LATS1 的 N 端调节 (NTR) 结构域之间的复合物。全长 MOB1B 的结构显示，N 端延伸形成短的 β 链（SN 链），后面是长的构象灵活的带正电接头和 α 螺旋（Switch 螺旋），它阻断 MOB1B 的 LATS1 结合表面。 Switch 螺旋通过 SN 链与 MOB1 核心结构域的 S2 链形成 β 片层来稳定。 Thr12 和 Thr35 残基的磷酸化在结构上通过“拉绳”机制加速 Switch 螺旋从 LATS1 结合表面的解离，从而实现 LATS1 结合。
MOB1 protein is a key regulator of large tumor suppressor 1/2 (LATS1/2) kinases in the Hippo pathway. MOB1 is present in an autoinhibited form and is activated by MST1/2-mediated phosphorylation, although the precise mechanisms responsible for autoinhibition and activation are unknown due to lack of an autoinhibited MOB1 structure. Here, we report on the crystal structure of full-length MOB1B in the autoinhibited form and a complex between the MOB1B core domain and the N-terminal regulation (NTR) domain of LATS1. The structure of full-length MOB1B shows that the N-terminal extension forms a short β-strand, the SN strand, followed by a long conformationally flexible positively-charged linker and α-helix, the Switch helix, which blocks the LATS1 binding surface of MOB1B. The Switch helix is stabilized by β-sheet formation of the SN strand with the S2 strand of the MOB1 core domain. Phosphorylation of Thr12 and Thr35 residues structurally accelerates dissociation of the Switch helix from the LATS1-binding surface by the “pull-the-string” mechanism, thereby enabling LATS1 binding.