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C500451200v1
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Papers In Press, published online ahead of print February 7, 2006
J. Biol. Chem, 10.1074/jbc.C500451200
Submitted on November 21, 2005
Revised on February 3, 2006
Accepted on February 7, 2006

TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase

Huira Chong-Kopera, Ken Inoki, Yong Li, Tianqing Zhu, Francesc R Garcia-Gonzalo, Jose Luis Rosa, and Kun-Liang Guan

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109

Corresponding Author: kunliang{at}umich.edu

Tuberous Sclerosis complex (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs. The 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 mTOR pathway. TSC1 is known to stabilize TSC2 by forming a complex with TSC2, which is a GAP for the Rheb small GTPase. We have identified HERC1 as a TSC2 interacting protein. HERC1 is a 532kDa protein with an E3 ubiquitin ligase 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 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.


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