6SSH

Structure of the TSC2 GAP domain

6SSH の概要

• エントリーDOI: 10.2210/pdb6ssh/pdb
• 分子名称: GTPase activator-like protein, 1,2-ETHANEDIOL (3 entities in total)
• 機能のキーワード: gtpase activating protein, signaling protein
• 由来する生物種: Chaetomium thermophilum
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23679.03

構造登録者

Hansmann, P.,Kiontke, S.,Kummel, D. (登録日: 2019-09-06, 公開日: 2020-05-27, 最終更新日: 2024-01-24)

主引用文献

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

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: 32502382
DOI: 10.1016/j.str.2020.05.008

実験手法

X-RAY DIFFRACTION (1.4 Å)