The crystal structure of the FERM and C-terminal domain complex of Drosophila Merlin
The crystal structure of the FERM and C-terminal domain complex of Drosophila Merlin
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果蝇 Merlin FERM 和 C 端结构域复合物的晶体结构
DOI：
10.1016/j.bbrc.2021.03.065
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发表时间：
2021
影响因子：
3.1
通讯作者：
Zhou Hao
中科院分区：
文献类型：
--
作者：
Zhang Fayou;Liu Beibei;Gao Yaqi;Long Jiafu;Zhou Hao
NF 2/Merlin是hippo通路的上游调节因子，具有自抑制的“封闭”状态和主动的“开放”状态。先前的研究表明果蝇Merlin采取了一种更封闭的构象。然而，构象调控的分子机制仍然知之甚少。在这里，我们首先证实了FERM和Merlin的C-末端结构域（CTD）之间的强相互作用，然后确定了FERM/CTD复合物的晶体结构，这揭示了Merlin采用比其人类同源NF 2更封闭构象的结构基础。有趣的是，我们发现Merlin的保守脂质结合位点可能被接头所掩盖。共聚焦分析证实，所有假定的脂质结合位点是非常重要的膜定位的梅林。此外，我们发现，磷酸模拟的Thr 616 Asp突变减弱了FERM和Merlin的CTD之间的相互作用。总之，FERM/CTD复合物的晶体结构不仅为Merlin的功能休眠构象提供了机制解释，也为揭示Merlin的构象调控机制奠定了基础。
NF2/Merlin is an upstream regulator of hippo pathway, and it has two states: an auto-inhibited “closed” state and an active “open” form. Previous studies showed thatDrosophilaMerlin adopts a more closed conformation. However, the molecular mechanism of conformational regulation remains poorly understood. Here, we first confirmed the strong interaction between FERM and the C-terminal domain (CTD) of Merlin, and then determined the crystal structure of the FERM/CTD complex, which reveals the structural basis of Merlin adopting a more closed conformation compared to its human cognate NF2. Interestingly, we found that the conserved lipid-binding site of Merlin might be masked by a linker. Confocal analyses confirmed that all putative lipid-binding site are very important for the membranal location of Merlin. More, we found that the phosphomimic Thr616Asp mutation weakens the interaction between FERM and CTD of Merlin. Collectively, the crystal structure of the FERM/CTD complex not only provides a mechanistic explanation of functionally dormant conformation of Merlin may also serve as a foundation for revealing the mechanism of conformational regulation of Merlin.