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Structural insights into TSC complex assembly and GAP activity on Rheb

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العنوان:	Structural insights into TSC complex assembly and GAP activity on Rheb
المؤلفون:	Zishuo Yu, Huirong Yang, Xizi Chen, Ning Gao, Yanhui Xu, Hai-Xin Yuan, Ningning Li, Kun-Liang Guan, Jiaxuan Cheng, Jiabei Li, Dan Ye
المصدر:	Nature Communications Nature communications, vol 12, iss 1 Nature Communications, Vol 12, Iss 1, Pp 1-10 (2021)
سنة النشر:	2020
مصطلحات موضوعية:	0301 basic medicine, Models, Molecular, GTP', General Physics and Astronomy, mTORC1, GTPase, Tuberous Sclerosis Complex 1 Protein, Cell growth, Tuberous Sclerosis, Models, Cryoelectron microscopy, Small GTPase, Tumour-suppressor proteins, Multidisciplinary, biology, Chemistry, GTPase-Activating Proteins, medicine.anatomical_structure, RHEB, Protein Binding, Cell signalling, congenital, hereditary, and neonatal diseases and abnormalities, Science, 1.1 Normal biological development and functioning, Protein domain, General Biochemistry, Genetics and Molecular Biology, Article, Vaccine Related, 03 medical and health sciences, Rare Diseases, Protein Domains, Underpinning research, Biodefense, Tuberous Sclerosis Complex 2 Protein, medicine, Humans, 030102 biochemistry & molecular biology, Prevention, Molecular, General Chemistry, Brain Disorders, nervous system diseases, 030104 developmental biology, HEK293 Cells, biology.protein, Biophysics, Biocatalysis, Ras Homolog Enriched in Brain Protein, TSC1, TSC2, Protein Multimerization
الوصف:	Tuberous sclerosis complex (TSC) integrates upstream stimuli and regulates cell growth by controlling the activity of mTORC1. TSC complex functions as a GTPase-activating protein (GAP) towards small GTPase Rheb and inhibits Rheb-mediated activation of mTORC1. Mutations in TSC genes cause tuberous sclerosis. In this study, the near-atomic resolution structure of human TSC complex reveals an arch-shaped architecture, with a 2:2:1 stoichiometry of TSC1, TSC2, and TBC1D7. This asymmetric complex consists of two interweaved TSC1 coiled-coil and one TBC1D7 that spans over the tail-to-tail TSC2 dimer. The two TSC2 GAP domains are symmetrically cradled within the core module formed by TSC2 dimerization domain and central coiled-coil of TSC1. Structural and biochemical analyses reveal TSC2 GAP-Rheb complimentary interactions and suggest a catalytic mechanism, by which an asparagine thumb (N1643) stabilizes γ-phosphate of GTP and accelerate GTP hydrolysis of Rheb. Our study reveals mechanisms of TSC complex assembly and GAP activity. Tuberous sclerosis complex (TSC) regulates cell growth by controlling the activity of mTORC1. The structure of human TSC complex reveals an arch-shaped, asymmetric architecture and a 2:2:1 stoichiometry of TSC1, TSC2, and TBC1D7 subunits and suggests a mechanism by which TSC2 accelerates GTP hydrolysis against a small GTPase Rheb.
وصف الملف:	application/pdf
تدمد:	2041-1723
الوصول الحر:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::31f5b1e548f704a6eddafca2d7a0d152Test https://pubmed.ncbi.nlm.nih.gov/33436626Test
حقوق:	OPEN
رقم الانضمام:	edsair.doi.dedup.....31f5b1e548f704a6eddafca2d7a0d152
قاعدة البيانات:	OpenAIRE

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