6SSH
Structure of the TSC2 GAP domain
Summary for 6SSH
| Entry DOI | 10.2210/pdb6ssh/pdb |
| Descriptor | GTPase activator-like protein, 1,2-ETHANEDIOL (3 entities in total) |
| Functional Keywords | gtpase activating protein, signaling protein |
| Biological source | Chaetomium thermophilum |
| Total number of polymer chains | 1 |
| Total formula weight | 23679.03 |
| Authors | Hansmann, P.,Kiontke, S.,Kummel, D. (deposition date: 2019-09-06, release date: 2020-05-27, Last modification date: 2024-01-24) |
| Primary citation | Hansmann, P.,Bruckner, A.,Kiontke, S.,Berkenfeld, B.,Seebohm, G.,Brouillard, P.,Vikkula, M.,Jansen, F.E.,Nellist, M.,Oeckinghaus, A.,Kummel, D. Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations. Structure, 28:933-942.e4, 2020 Cited by PubMed Abstract: The TSC complex is the cognate GTPase-activating protein (GAP) for the small GTPase Rheb and a crucial regulator of the mechanistic target of rapamycin complex 1 (mTORC1). Mutations in the TSC1 and TSC2 subunits of the complex cause tuberous sclerosis complex (TSC). We present the crystal structure of the catalytic asparagine-thumb GAP domain of TSC2. A model of the TSC2-Rheb complex and molecular dynamics simulations suggest that TSC2 Asn1643 and Rheb Tyr35 are key active site residues, while Rheb Arg15 and Asp65, previously proposed as catalytic residues, contribute to the TSC2-Rheb interface and indirectly aid catalysis. The TSC2 GAP domain is further stabilized by interactions with other TSC2 domains. We characterize TSC2 variants that partially affect TSC2 functionality and are associated with atypical symptoms in patients, suggesting that mutations in TSC1 and TSC2 might predispose to neurological and vascular disorders without fulfilling the clinical criteria for TSC. PubMed: 32502382DOI: 10.1016/j.str.2020.05.008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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