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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-30708 | |||||||||
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Title | Cryo-EM structure of human TSC complex | |||||||||
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![]() | TSC complex / Regulator of cell growth / GTPase-activating protein / Elongated arch-shaped fold / GENE REGULATION | |||||||||
Function / homology | ![]() 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 / 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 / ATPase inhibitor activity / cardiac muscle cell differentiation / negative regulation of ATP-dependent activity / 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 / protein folding chaperone complex / anoikis / negative regulation of TOR signaling / TBC/RABGAPs / negative regulation of mitophagy / regulation of small GTPase mediated signal transduction / AKT phosphorylates targets in the cytosol / negative regulation of macroautophagy / Macroautophagy / positive chemotaxis / negative regulation of Wnt signaling pathway / glucose import / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of focal adhesion assembly / associative learning / regulation of endocytosis / positive regulation of macroautophagy / 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 / Hsp70 protein binding / myelination / viral process / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to starvation / GTPase activator activity / lipid droplet / adult locomotory behavior / cell-matrix adhesion / insulin-like growth factor receptor signaling pathway / ciliary basal body / positive regulation of GTPase activity / positive regulation of protein ubiquitination / kidney development / neural tube closure / hippocampus development / TP53 Regulates Metabolic Genes / synapse organization / negative regulation of protein kinase activity / Hsp90 protein binding / response to insulin / potassium ion transport / cerebral cortex development / small GTPase binding / endocytosis / protein import into nucleus / protein localization / lamellipodium / regulation of translation / heart development / protein-folding chaperone binding / cell cortex / cytoplasmic vesicle / adaptive immune response / cell population proliferation / postsynaptic density / lysosome / protein stabilization / regulation of cell cycle / negative regulation of translation / 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 | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 4.4 Å | |||||||||
![]() | Yang H / Yu Z / Chen X / Li J / Li N / Cheng J / Gao N / Yuan H / Ye D / Guan K / Xu Y | |||||||||
![]() | ![]() 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 |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 501.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17 KB 17 KB | Display Display | ![]() |
Images | ![]() | 19.3 KB | ||
Filedesc metadata | ![]() | 7.1 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7dl2MC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.356 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Cryo-EM structure of human TSC complex
Entire | Name: Cryo-EM structure of human TSC complex |
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Components |
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-Supramolecule #1: Cryo-EM structure of human TSC complex
Supramolecule | Name: Cryo-EM structure of human TSC complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Hamartin
Macromolecule | Name: Hamartin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 129.945367 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MAQQANVGEL LAMLDSPMLG VRDDVTAVFK ENLNSDRGPM LVNTLVDYYL ETSSQPALHI LTTLQEPHDK HLLDRINEYV GKAATRLSI LSLLGHVIRL QPSWKHKLSQ APLLPSLLKC LKMDTDVVVL TTGVLVLITM LPMIPQSGKQ HLLDFFDIFG R LSSWCLKK ...String: MAQQANVGEL LAMLDSPMLG VRDDVTAVFK ENLNSDRGPM LVNTLVDYYL ETSSQPALHI LTTLQEPHDK HLLDRINEYV GKAATRLSI LSLLGHVIRL QPSWKHKLSQ APLLPSLLKC LKMDTDVVVL TTGVLVLITM LPMIPQSGKQ HLLDFFDIFG R LSSWCLKK PGHVAEVYLV HLHASVYALF HRLYGMYPCN FVSFLRSHYS MKENLETFEE VVKPMMEHVR IHPELVTGSK DH ELDPRRW KRLETHDVVI ECAKISLDPT EASYEDGYSV SHQISARFPH RSADVTTSPY ADTQNSYGCA TSTPYSTSRL MLL NMPGQL PQTLSSPSTR LITEPPQATL WSPSMVCGMT TPPTSPGNVP PDLSHPYSKV FGTTAGGKGT PLGTPATSPP PAPL CHSDD YVHISLPQAT VTPPRKEERM DSARPCLHRQ HHLLNDRGSE EPPGSKGSVT LSDLPGFLGD LASEEDSIEK DKEEA AISR ELSEITTAEA EPVVPRGGFD SPFYRDSLPG SQRKTHSAAS SSQGASVNPE PLHSSLDKLG PDTPKQAFTP IDLPCG SAD ESPAGDRECQ TSLETSIFTP SPCKIPPPTR VGFGSGQPPP YDHLFEVALP KTAHHFVIRK TEELLKKAKG NTEEDGV PS TSPMEVLDRL IQQGADAHSK ELNKLPLPSK SVDWTHFGGS PPSDEIRTLR DQLLLLHNQL LYERFKRQQH ALRNRRLL R KVIKAAALEE HNAAMKDQLK LQEKDIQMWK VSLQKEQARY NQLQEQRDTM VTKLHSQIRQ LQHDREEFYN QSQELQTKL EDCRNMIAEL RIELKKANNK VCHTELLLSQ VSQKLSNSES VQQQMEFLNR QLLVLGEVNE LYLEQLQNKH SDTTKEVEMM KAAYRKELE KNRSHVLQQT QRLDTSQKRI LELESHLAKK DHLLLEQKKY LEDVKLQARG QLQAAESRYE AQKRITQVFE L EILDLYGR LEKDGLLKKL EEEKAEAAEA AEERLDCCND GCSDSMVGHN EEASGHNGET KTPRPSSARG SSGSRGGGGS SS SSSELST PEKPPHQRAG PFSSRWETTM GEASASIPTT VGSLPSSKSF LGMKARELFR NKSESQCDED GMTSSLSESL KTE LGKDLG VEAKIPLNLD GPHPSPPTPD SVGQLHIMDY NETHHEHS UniProtKB: Hamartin |
-Macromolecule #2: Isoform 7 of Tuberin
Macromolecule | Name: Isoform 7 of Tuberin / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 188.182312 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MECGLNNRIR MIGQICEVAK TKKFEEHAVE ALWKAVADLL QPERPLEARH AVLALLKAIV QGQGERLGVL RALFFKVIKD YPSNEDLHE RLEVFKALTD NGRHITYLEE ELADFVLQWM DVGLSSEFLL VLVNLVKFNS CYLDEYIARM VQMICLLCVR T ASSVDIEV ...String: MECGLNNRIR MIGQICEVAK TKKFEEHAVE ALWKAVADLL QPERPLEARH AVLALLKAIV QGQGERLGVL RALFFKVIKD YPSNEDLHE RLEVFKALTD NGRHITYLEE ELADFVLQWM DVGLSSEFLL VLVNLVKFNS CYLDEYIARM VQMICLLCVR T ASSVDIEV SLQVLDAVVC YNCLPAESLP LFIVTLCRTI NVKELCEPCW KLMRNLLGTH LGHSAIYNMC HLMEDRAYME DA PLLRGAV FFVGMALWGA HRLYSLRNSP TSVLPSFYQA MACPNEVVSY EIVLSITRLI KKYRKELQVV AWDILLNIIE RLL QQLQTL DSPELRTIVH DLLTTVEELC DQNEFHGSQE RYFELVERCA DQRPESSLLN LISYRAQSIH PAKDGWIQNL QALM ERFFR SESRGAVRIK VLDVLSFVLL INRQFYEEEL INSVVISQLS HIPEDKDHQV RKLATQLLVD LAEGCHTHHF NSLLD IIEK VMARSLSPPP ELEERDVAAY SASLEDVKTA VLGLLVILQT KLYTLPASHA TRVYEMLVSH IQLHYKHSYT LPIASS IRL QAFDFLLLLR ADSLHRLGLP NKDGVVRFSP YCVCDYMEPE RGSEKKTSGP LSPPTGPPGP APAGPAVRLG SVPYSLL FR VLLQCLKQES DWKVLKLVLG RLPESLRYKV LIFTSPCSVD QLCSALCSML SGPKTLERLR GAPEGFSRTD LHLAVVPV L TALISYHNYL DKTKQREMVY CLEQGLIHRC ASQCVVALSI CSVEMPDIII KALPVLVVKL THISATASMA VPLLEFLST LARLPHLYRN FAAEQYASVF AISLPYTNPS KFNQYIVCLA HHVIAMWFIR CRLPFRKDFV PFITKGLRSN VLLSFDDTPE KDSFRARST SLNERPKSRI QTSLTSASLG SADENSVAQA DDSLKNLHLE LTETCLDMMA RYVFSNFTAV PKRSPVGEFL L AGGRTKTW LVGNKLVTVT TSVGTGTRSL LGLDSGELQS GPESSSSPGV HVRQTKEAPA KLESQAGQQV SRGARDRVRS MS GGHGLRV GALDVPASQF LGSATSPGPR TAPAAKPEKA SAGTRVPVQE KTNLAAYVPL LTQGWAEILV RRPTGNTSWL MSL ENPLSP FSSDINNMPL QELSNALMAA ERFKEHRDTA LYKSLSVPAA STAKPPPLPR SNTDSAVVME EGSPGEVPVL VEPP GLEDV EAALGMDRRT DAYSRSSSVS SQEEKSLHAE ELVGRGIPIE RVVSSEGGRP SVDLSFQPSQ PLSKSSSSPE LQTLQ DILG DPGDKADVGR LSPEVKARSQ SGTLDGESAA WSASGEDSRG QPEGPLPSSS PRSPSGLRPR GYTISDSAPS RRGKRV ERD ALKSRATASN AEKVPGINPS FVFLQLYHSP FFGDESNKPI LLPNESQSFE RSVQLLDQIP SYDTHKIAVL YVGEGQS NS ELAILSNEHG SYRYTEFLTG LGRLIELKDC QPDKVYLGGL DVCGEDGQFT YCWHDDIMQA VFHIATLMPT KDVDKHRC D KKRHLGNDFV SIVYNDSGED FKLGTIKGQF NFVHVIVTPL DYECNLVSLQ CRKDMEGLVD TSVAKIVSDR NLPFVARQM ALHANMASQV HHSRSNPTDI YPSKWIARLR HIKRLRQRIC EEAAYSNPSL PLVHPPSHSK APAQTPAEPT PGYEVGQRKR LISSVEDFT EFV UniProtKB: Tuberin |
-Macromolecule #3: TBC1 domain family member 7
Macromolecule | Name: TBC1 domain family member 7 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 30.911129 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: GVEEKKSLEI LLKDDRLDTE KLCTFSQRFP LPSMYRALVW KVLLGILPPH HESHAKVMMY RKEQYLDVLH ALKVVRFVSD ATPQAEVYL RMYQLESGKL PRSPSFPLEP DDEVFLAIAK AMEEMVEDSV DCYWITRRFV NQLNTKYRDS LPQLPKAFEQ Y LNLEDGRL ...String: GVEEKKSLEI LLKDDRLDTE KLCTFSQRFP LPSMYRALVW KVLLGILPPH HESHAKVMMY RKEQYLDVLH ALKVVRFVSD ATPQAEVYL RMYQLESGKL PRSPSFPLEP DDEVFLAIAK AMEEMVEDSV DCYWITRRFV NQLNTKYRDS LPQLPKAFEQ Y LNLEDGRL LTHLRMCSAA PKLPYDLWFK RCFAGCLPES SLQRVWDKVV SGSCKILVFV AVEILLTFKI KVMALNSAEK IT KFLENIP QDSSDAIVSK AIDLWHKHCG UniProtKB: TBC1 domain family member 7 |
-Macromolecule #4: unknown protein
Macromolecule | Name: unknown protein / type: protein_or_peptide / ID: 4 Details: The author does not know what chain F is derived from. Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 22.230297 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) ...String: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK) |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 131022 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |