Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis.

ABSTRACT: Tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes. The gene products hamartin and tuberin form the TSC complex that acts as GTPase-activating protein for Rheb and negatively regulates the mammalian target of rapamycin complex 1 (mTORC1). Tuberin contains a RapGAP homology domain responsible for inactivation of Rheb, but functions of other protein domains remain elusive. Here we show that the TSC2 N terminus interacts with the TSC1 C terminus to mediate complex formation. The structure of the TSC2 N-terminal domain from Chaetomium thermophilum and a homology model of the human tuberin N terminus are presented. We characterize the molecular requirements for TSC1-TSC2 interactions and analyze pathological point mutations in tuberin. Many mutat

SUBMITTER: Zech R 

PROVIDER: S-EPMC5025687 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature