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A WW Tandem-Mediated Dimerization Mode of SAV1 Essential for Hippo Signaling.
Cell Reports ( IF 8.8 ) Pub Date : 2020-09-08 , DOI: 10.1016/j.celrep.2020.108118
Zhijie Lin 1 , Ruiling Xie 2 , Kunliang Guan 3 , Mingjie Zhang 4
Affiliation  

The canonical mammalian Hippo pathway contains a core kinase signaling cascade requiring upstream MST to form a stable complex with SAV1 in order to phosphorylate the downstream LATS/MOB complex. Though SAV1 dimerization is essential for the trans-activation of MST, the molecular mechanism underlying SAV1 dimerization is unclear. Here, we discover that the SAV1 WW tandem containing a short Pro-rich extension immediately following the WW tandem (termed as “WW12ex”) forms a highly stable homodimer. The crystal structure of SAV1 WW12ex reveals that the Pro-rich extension of one subunit binds to both WW domains from the other subunit. Thus, SAV1 WW12ex forms a domain-swapped dimer instead of a WW2 homodimerization-mediated dimer. The WW12ex-mediated dimerization of SAV1 is required for the MST/SAV1 complex assembly and MST kinase activation. Finally, we show that several cancer-related SAV1 variants disrupt SAV1 dimer formation, and thus, these mutations may impair the tumor-suppression activity of SAV1.



中文翻译:

WW串联介导的SAV1二聚化模式,对河马信号至关重要。

规范的哺乳动物河马途径包含核心激酶信号传导级联,其​​需要上游MST与SAV1形成稳定的复合物才能磷酸化下游的LATS / MOB复合物。尽管SAV1二聚化对于MST的反式激活至关重要,但是尚不清楚SAV1二聚化的分子机制。在这里,我们发现SAV1 WW串联序列包含紧随WW串联序列(称为“ WW12ex”)后短的Pro-rich延伸序列,形成了高度稳定的同源二聚体。SAV1 WW12ex的晶体结构表明,一个亚基的Pro-rich延伸序列与另一亚基的两个WW域结合。因此,SAV1 WW12ex形成域交换的二聚体,而不是WW2均二聚介导的二聚体。MST / SAV1复合物装配和MST激酶激活需要WW12ex介导的SAV1二聚化。最后,SAV1变体破坏SAV1二聚体的形成,因此,这些突变可能削弱SAV1的肿瘤抑制活性。

更新日期:2020-09-09
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