SAV1 的 WW 串联介导二聚化模式对 Hippo 信号通路至关重要。
A WW Tandem-Mediated Dimerization Mode of SAV1 Essential for Hippo Signaling.
机构信息
Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Otolaryngology, Head & Neck Surgery, Peking University First Hospital, Beijing 100034, China.
出版信息
Cell Rep. 2020 Sep 8;32(10):108118. doi: 10.1016/j.celrep.2020.108118.
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.
经典的哺乳动物 Hippo 信号通路包含一个核心激酶信号级联反应，需要上游 MST 与 SAV1 形成稳定的复合物，以便磷酸化下游的 LATS/MOB 复合物。虽然 SAV1 二聚化对于 MST 的转激活是必需的，但 SAV1 二聚化的分子机制尚不清楚。在这里，我们发现 SAV1 的 WW 串联结构域中含有紧接着 WW 串联结构域的短脯氨酸富集延伸（称为“WW12ex”），形成高度稳定的同源二聚体。SAV1 WW12ex 的晶体结构揭示了一个亚基的脯氨酸富集延伸与另一个亚基的两个 WW 结构域结合。因此，SAV1 WW12ex 形成的是一个结构域交换二聚体，而不是通过 WW2 同源二聚化介导的二聚体。SAV1 的 WW12ex 介导的二聚化对于 MST/SAV1 复合物的组装和 MST 激酶的激活是必需的。最后，我们表明，几种与癌症相关的 SAV1 变体破坏了 SAV1 二聚体的形成，因此，这些突变可能会削弱 SAV1 的肿瘤抑制活性。
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