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- PDB-7dl2: Cryo-EM structure of human TSC complex -

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Basic information

Entry
Database: PDB / ID: 7dl2
TitleCryo-EM structure of human TSC complex
Components
  • Hamartin
  • Isoform 7 of Tuberin
  • TBC1 domain family member 7
  • unknown protein
KeywordsGENE REGULATION / TSC complex / Regulator of cell growth / GTPase-activating protein / Elongated arch-shaped fold
Function / homology
Function and homology information


memory T cell differentiation / TSC1-TSC2 complex / Inhibition of TSC complex formation by PKB / : / cellular response to decreased oxygen levels / regulation of insulin receptor signaling pathway / negative regulation of cilium assembly / regulation of cell-matrix adhesion / negative regulation of ATP-dependent activity / ATPase inhibitor activity ...memory T cell differentiation / TSC1-TSC2 complex / Inhibition of TSC complex formation by PKB / : / cellular response to decreased oxygen levels / regulation of insulin receptor signaling pathway / negative regulation of cilium assembly / regulation of cell-matrix adhesion / negative regulation of ATP-dependent activity / ATPase inhibitor activity / cardiac muscle cell differentiation / cell projection organization / Energy dependent regulation of mTOR by LKB1-AMPK / response to growth factor / negative regulation of cell size / regulation of stress fiber assembly / activation of GTPase activity / negative regulation of TOR signaling / anoikis / negative regulation of mitophagy / regulation of small GTPase mediated signal transduction / protein folding chaperone complex / TBC/RABGAPs / AKT phosphorylates targets in the cytosol / negative regulation of macroautophagy / positive chemotaxis / Macroautophagy / negative regulation of Wnt signaling pathway / D-glucose import / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of focal adhesion assembly / associative learning / positive regulation of macroautophagy / regulation of endocytosis / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / phosphatase binding / ribosomal subunit export from nucleus / vesicle-mediated transport / negative regulation of insulin receptor signaling pathway / negative regulation of TORC1 signaling / protein folding chaperone / myelination / Hsp70 protein binding / phosphatidylinositol 3-kinase/protein kinase B signal transduction / GTPase activator activity / cellular response to starvation / lipid droplet / cell-matrix adhesion / insulin-like growth factor receptor signaling pathway / positive regulation of GTPase activity / adult locomotory behavior / ciliary basal body / positive regulation of protein ubiquitination / kidney development / neural tube closure / TP53 Regulates Metabolic Genes / hippocampus development / negative regulation of protein kinase activity / response to insulin / synapse organization / Hsp90 protein binding / potassium ion transport / cerebral cortex development / small GTPase binding / protein import into nucleus / endocytosis / protein localization / lamellipodium / regulation of translation / heart development / protein-folding chaperone binding / cell cortex / cytoplasmic vesicle / adaptive immune response / cell population proliferation / negative regulation of translation / postsynaptic density / lysosome / regulation of cell cycle / protein stabilization / negative regulation of cell population proliferation / lysosomal membrane / perinuclear region of cytoplasm / Golgi apparatus / protein homodimerization activity / protein-containing complex / membrane / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tuberin / Tuberin-type domain / Tuberin, N-terminal / Tuberin/Ral GTPase-activating protein subunit alpha / Tuberin / Domain of unknown function (DUF3384) / Rap/Ran-GAP domain / Rap/Ran-GAP superfamily / TBC1 domain family member 7 / TBC1 domain family member 7, domain 2 ...Tuberin / Tuberin-type domain / Tuberin, N-terminal / Tuberin/Ral GTPase-activating protein subunit alpha / Tuberin / Domain of unknown function (DUF3384) / Rap/Ran-GAP domain / Rap/Ran-GAP superfamily / TBC1 domain family member 7 / TBC1 domain family member 7, domain 2 / Rap/ran-GAP / Rap GTPase activating proteins domain profile. / Hamartin / Hamartin protein / Rab-GTPase-TBC domain / Rab-GTPase-TBC domain superfamily / Rab-GTPase-TBC domain / TBC/rab GAP domain profile. / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
Tuberin / Hamartin / TBC1 domain family member 7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsYang, H. / Yu, Z. / Chen, X. / Li, J. / Li, N. / Cheng, J. / Gao, N. / Yuan, H. / Ye, D. / Guan, K. / Xu, Y.
CitationJournal: Nat Commun / Year: 2021
Title: Structural insights into TSC complex assembly and GAP activity on Rheb.
Authors: Huirong Yang / Zishuo Yu / Xizi Chen / Jiabei Li / Ningning Li / Jiaxuan Cheng / Ning Gao / Hai-Xin Yuan / Dan Ye / Kun-Liang Guan / Yanhui Xu /
Abstract: 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 ...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.
History
DepositionNov 25, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
D: Hamartin
A: Isoform 7 of Tuberin
B: Isoform 7 of Tuberin
C: Hamartin
E: TBC1 domain family member 7
F: unknown protein


Theoretical massNumber of molelcules
Total (without water)689,3976
Polymers689,3976
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area26340 Å2
ΔGint-186 kcal/mol
Surface area152750 Å2

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Components

#1: Protein Hamartin / Tuberous sclerosis 1 protein


Mass: 129945.367 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TSC1, KIAA0243, TSC / Production host: Homo sapiens (human) / References: UniProt: Q92574
#2: Protein Isoform 7 of Tuberin / Tuberous sclerosis 2 protein


Mass: 188182.312 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TSC2, TSC4 / Production host: Homo sapiens (human) / References: UniProt: P49815
#3: Protein TBC1 domain family member 7 / Cell migration-inducing protein 23


Mass: 30911.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TBC1D7, TBC7, HSPC239 / Production host: Homo sapiens (human) / References: UniProt: Q9P0N9
#4: Protein unknown protein


Mass: 22230.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The author does not know what chain F is derived from.
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
Sequence detailsThe author does not know the sequence of chain F.

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of human TSC complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 131022 / Symmetry type: POINT

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