Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations.
GTPase-activating protein
Rheb
TSC
mTORC1
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
04 08 2020
04 08 2020
Historique:
received:
02
10
2019
revised:
06
02
2020
accepted:
15
05
2020
pubmed:
6
6
2020
medline:
29
7
2021
entrez:
6
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32502382
pii: S0969-2126(20)30177-5
doi: 10.1016/j.str.2020.05.008
pii:
doi:
Substances chimiques
RHEB protein, human
0
Ras Homolog Enriched in Brain Protein
0
TSC2 protein, human
0
Tuberous Sclerosis Complex 2 Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
933-942.e4Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no conflict of interest.