TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase
TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase
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DOI：
10.1074/jbc.c500451200
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发表时间：
2006-03-31
影响因子：
4.8
通讯作者：
Guan, KL
中科院分区：
文献类型：
--
作者：
Chong-Kopera, H;Inoki, K;Guan, KL
结节性硬化症（TSC）是一种常染色体显性遗传病，其特征是在各器官形成错构瘤。已经确定了导致这种疾病的两个基因，TSC1和TSC2。TSC1和TSC2蛋白，也分别被称为hamartin和tuberin，已被证明通过抑制哺乳动物雷帕霉素途径靶点来调节细胞生长。已知TSC1通过与TSC2形成复合物来稳定TSC2， TSC2是Rheb小GTPase的GTPase激活蛋白。我们已经确定HERC1是一种与TSC2相互作用的蛋白。HERC1是一种532- kDa蛋白，其E3泛素连接酶与E6AP羧基端（HECT）结构域同源。我们观察到TSC1与TSC2的相互作用似乎排除了TSC2与HERC1的相互作用。TSC2的疾病突变导致其不稳定，允许在TSC1存在的情况下与HERC1结合。我们的研究揭示了TSC1如何通过从TSC2复合体中排除HERC1泛素连接酶来稳定TSC2的潜在分子机制。此外，这些数据揭示了某些疾病突变如何灭活TSC2的可能的生化基础。
Tuberous sclerosis complex ( TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs. Two genes responsible for the disease, TSC1 and TSC2, have been identified. The TSC1 and TSC2 proteins, also called hamartin and tuberin, respectively, have been shown to regulate cell growth through inhibition of the mammalian target of rapamycin pathway. TSC1 is known to stabilize TSC2 by forming a complex with TSC2, which is a GTPase- activating protein for the Rheb small GTPase. We have identified HERC1 as a TSC2- interacting protein. HERC1 is a 532- kDa protein with an E3 ubiquitin ligase homology to E6AP carboxyl terminus ( HECT) domain. We observed that the interaction of TSC1 with TSC2 appears to exclude TSC2 from interacting with HERC1. Disease mutations in TSC2, which result in its destabilization, allow binding to HERC1 in the presence of TSC1. Our study reveals a potential molecular mechanism of how TSC1 stabilizes TSC2 by excluding the HERC1 ubiquitin ligase from the TSC2 complex. Furthermore, these data reveal a possible biochemical basis of how certain disease mutations inactivate TSC2.