Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region
Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region
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TBC1D7-TSC1 复合物的结构表明，TBC1D7 稳定了 TSC1 C 末端卷曲线圈区域的二聚化。
DOI：
10.1093/jmcb/mjw001
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发表时间：
2016-10-01
影响因子：
5.5
通讯作者：
Wu, Geng
中科院分区：
文献类型：
--
作者：
Gai, Zhongchao;Chu, Wendan;Wu, Geng
TSC1和TSC2突变是结节性硬化症复杂病例的主要原因。TSC1和TSC2蛋白组装成一个复合体，由TBC1D7通过与TSC1卷曲线圈(CC)区域的直接相互作用而稳定。TBC1D7的缺失与智力残疾和巨脑畸形有关。在这里，我们确定了TBC1D7与TSC1-CC的C-末端部分(残基939-992)之间的配合物的晶体结构。结构表明，两个TSC1-CCS形成一个平行的同源二聚体，这导致形成两个对称的表面与TBC1D7相互作用。TbC1D7利用其α4和α5螺旋主要通过疏水作用与一个Tsc1(939-992)分子的α1螺旋相互作用，并利用其α4螺旋的C末端与另一个Tsc1(939-992)分子结合。生化和细胞生物学数据表明，TBC1D7确实在很大程度上稳定了TSC1-CC的同源二聚，关键界面残基的突变大大削弱了这一作用。综上所述，我们的数据揭示了TBC1D7介导的TSC1二聚稳定的分子机制，以及它对全息-TSC复合体结构完整性的贡献。
TSC1 and TSC2 mutations account for the majority of tuberous sclerosis complex cases. The TSC1 and TSC2 proteins assemble into a complex that is stabilized by TBC1D7 through its direct interaction with the TSC1 coiled coil (CC) region. Loss of TBC1D7 is associated with intellectual disability and megalencephaly. Here, we determine the crystal structure of the complex between TBC1D7 and the C-terminal part (residues 939-992) of TSC1-CC. The structure reveals that two TSC1-CCs form a parallel homodimer, which results in the formation of two symmetric surfaces for interaction with TBC1D7. TBC1D7 employs its α4 and α5 helices to interact with the α1 helix of one TSC1 (939-992) molecule mainly through hydrophobic interactions, and simultaneously associates with the other TSC1 (939-992) molecule using the C-terminal tip of its α4 helix. Biochemical and cell biological data demonstrate that TBC1D7 indeed substantially stabilizes the homodimerization of TSC1-CC, and mutations to the critical interface residues greatly compromise this effect. Together, our data reveal the molecular mechanism underlying TBC1D7-mediated stabilization of TSC1 dimerization, and its contribution to the structural integrity of the holo-TSC complex.