title: 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 mutations are structural and produce improperly folded protein, explaining their effect in pathology, but we identify one point mutant that abrogates complex formation without affecting protein structure. We provide the first structural information on TSC2/tuberin with novel insight into the molecular function.
authors: From the Structural Biology Section, FB5 Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany.
authors: Reinhard
authors: R
authors: Zech
authors: From the Structural Biology Section, FB5 Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany.
authors: Stephan
authors: S
authors: Kiontke
authors: Macromolecular Crystallography (BESSY-MX), Helmholtz-Zentrum Berlin für Materialien und Energie, 12489 Berlin, Germany, and.
authors: Uwe
authors: U
authors: Mueller
authors: Institute of Molecular Tumor Biology, Medical Faculty of the WWU Münster, 48149 Münster Germany.
authors: Andrea
authors: A
authors: Oeckinghaus
authors: From the Structural Biology Section, FB5 Biology/Chemistry, University of Osnabrück, 49076 Osnabrück, Germany, daniel.kuemmel@uos.de.
authors: Daniel
authors: D
authors: Kümmel
mesh_terms: D002597:Chaetomium / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D000076205:Ras Homolog Enriched in Brain Protein; D040681:Structural Homology, Protein; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014402:Tuberous Sclerosis; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins
keywords: hamartin; protein structure; protein-protein interaction; signaling; tuberin; tuberous sclerosis complex (TSC); x-ray crystallography