5HIU

Structure of the TSC2 N-terminus

Summary for 5HIU

• Entry DOI: 10.2210/pdb5hiu/pdb
• Descriptor: GTPase activator-like protein (2 entities in total)
• Functional Keywords: complex, signaling protein
• Biological source: Chaetomium thermophilum
• Total number of polymer chains: 4
• Total formula weight: 206189.34

Authors

Zech, R.,Kiontke, S.,Kummel, D. (deposition date: 2016-01-12, release date: 2016-08-10, Last modification date: 2024-05-08)

Primary citation

Zech, R.,Kiontke, S.,Mueller, U.,Oeckinghaus, A.,Kummel, D.
Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis.
J.Biol.Chem., 291:20008-20020, 2016

PubMed 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.

PubMed: 27493206
DOI: 10.1074/jbc.M116.732446

Experimental method

X-RAY DIFFRACTION (2.5 Å)