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- PDB-7ole: Cryo-EM structure of the TELO2-TTI1-TTI2-RUVBL1-RUVBL2 complex -

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Basic information

Entry
Database: PDB / ID: 7ole
TitleCryo-EM structure of the TELO2-TTI1-TTI2-RUVBL1-RUVBL2 complex
Components
  • (TELO2-interacting protein ...) x 2
  • RuvB-like 1
  • RuvB-like 2
  • Telomere length regulation protein TEL2 homolog
KeywordsCHAPERONE / R2TP / TTT / TELO2 / TTI1 / TTI2 / RUVBL1 / RUVBL2 / HSP90 chaperone / mTOR / PIKK / STRUCTURAL PROTEIN
Function / homology
Function and homology information


positive regulation of DNA damage checkpoint / 'de novo' cotranslational protein folding / promoter-enhancer loop anchoring activity / TTT Hsp90 cochaperone complex / telomerase RNA localization to Cajal body / regulation of DNA strand elongation / positive regulation of telomere maintenance in response to DNA damage / TORC2 complex / establishment of protein localization to chromatin / TORC1 complex ...positive regulation of DNA damage checkpoint / 'de novo' cotranslational protein folding / promoter-enhancer loop anchoring activity / TTT Hsp90 cochaperone complex / telomerase RNA localization to Cajal body / regulation of DNA strand elongation / positive regulation of telomere maintenance in response to DNA damage / TORC2 complex / establishment of protein localization to chromatin / TORC1 complex / R2TP complex / dynein axonemal particle / regulation of TOR signaling / Swr1 complex / RPAP3/R2TP/prefoldin-like complex / Ino80 complex / regulation of double-strand break repair / box C/D snoRNP assembly / protein folding chaperone complex / single-stranded 3'-5' DNA helicase activity / telomeric DNA binding / double-stranded DNA helicase activity / forked DNA-dependent helicase activity / regulation of chromosome organization / NuA4 histone acetyltransferase complex / regulation of DNA replication / TFIID-class transcription factor complex binding / four-way junction helicase activity / MLL1 complex / regulation of embryonic development / Telomere Extension By Telomerase / positive regulation of double-strand break repair via homologous recombination / RNA polymerase II core promoter sequence-specific DNA binding / regulation of DNA repair / Deposition of new CENPA-containing nucleosomes at the centromere / telomere maintenance / DNA helicase activity / positive regulation of DNA repair / TBP-class protein binding / DNA Damage Recognition in GG-NER / cellular response to estradiol stimulus / Hsp90 protein binding / chromatin DNA binding / negative regulation of canonical Wnt signaling pathway / Formation of the beta-catenin:TCF transactivating complex / euchromatin / ADP binding / beta-catenin binding / nuclear matrix / UCH proteinases / transcription corepressor activity / cellular response to UV / positive regulation of canonical Wnt signaling pathway / unfolded protein binding / nucleosome / protein folding / HATs acetylate histones / ATPase binding / spermatogenesis / regulation of apoptotic process / DNA recombination / molecular adaptor activity / DNA helicase / transcription coactivator activity / chromosome, telomeric region / Ub-specific processing proteases / regulation of cell cycle / protein stabilization / nuclear speck / nuclear body / ciliary basal body / chromatin remodeling / cadherin binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / ribonucleoprotein complex / cell division / DNA repair / centrosome / regulation of transcription by RNA polymerase II / regulation of DNA-templated transcription / protein kinase binding / protein-containing complex binding / positive regulation of DNA-templated transcription / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / extracellular exosome / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Tti2 family / Tti2 family / TEL2-interacting protein 1 / : / : / TELO2-interacting protein 1 / TTI1 N-terminal TPR domain / TELO2-interacting protein 1 homologue second TPR domain / TTI1 C-terminal TPR domain / TELO2 ARM repeat domain ...Tti2 family / Tti2 family / TEL2-interacting protein 1 / : / : / TELO2-interacting protein 1 / TTI1 N-terminal TPR domain / TELO2-interacting protein 1 homologue second TPR domain / TTI1 C-terminal TPR domain / TELO2 ARM repeat domain / Telomere length regulation protein, conserved domain / TEL2, C-terminal domain superfamily / : / Telomere length regulation protein / RuvBL1 DNA/RNA binding domain / RuvB-like / RuvB-like, AAA-lid domain / RuvBL1/2, DNA/RNA binding domain / TIP49 P-loop domain / TIP49 AAA-lid domain / TIP49, P-loop domain / Helicase, Ruva Protein; domain 3 - #60 / Helicase, Ruva Protein; domain 3 / Armadillo-like helical / OB fold (Dihydrolipoamide Acetyltransferase, E2P) / Armadillo-type fold / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Beta Barrel / P-loop containing nucleoside triphosphate hydrolase / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / TELO2-interacting protein 1 homolog / TELO2-interacting protein 2 / RuvB-like 2 / RuvB-like 1 / Telomere length regulation protein TEL2 homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsPal, M. / Llorca, O. / Pearl, L.
Funding support United Kingdom, Spain, 5items
OrganizationGrant numberCountry
Wellcome Trust095605/Z/11/Z United Kingdom
Wellcome Trust095605/Z/11/A United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R01678X/1 United Kingdom
Spanish Ministry of Science, Innovation, and UniversitiesSAF2017-82632-P Spain
European Regional Development FundY2018/BIO4747 Spain
CitationJournal: Cell Rep / Year: 2021
Title: Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone.
Authors: Mohinder Pal / Hugo Muñoz-Hernandez / Dennis Bjorklund / Lihong Zhou / Gianluca Degliesposti / J Mark Skehel / Emma L Hesketh / Rebecca F Thompson / Laurence H Pearl / Oscar Llorca / Chrisostomos Prodromou /
Abstract: The R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) complex, in collaboration with heat shock protein 90 (HSP90), functions as a chaperone for the assembly and stability of protein complexes, including RNA ...The R2TP (RUVBL1-RUVBL2-RPAP3-PIH1D1) complex, in collaboration with heat shock protein 90 (HSP90), functions as a chaperone for the assembly and stability of protein complexes, including RNA polymerases, small nuclear ribonucleoprotein particles (snRNPs), and phosphatidylinositol 3-kinase (PI3K)-like kinases (PIKKs) such as TOR and SMG1. PIKK stabilization depends on an additional complex of TELO2, TTI1, and TTI2 (TTT), whose structure and function are poorly understood. The cryoelectron microscopy (cryo-EM) structure of the human R2TP-TTT complex, together with biochemical experiments, reveals the mechanism of TOR recruitment to the R2TP-TTT chaperone. The HEAT-repeat TTT complex binds the kinase domain of TOR, without blocking its activity, and delivers TOR to the R2TP chaperone. In addition, TTT regulates the R2TP chaperone by inhibiting RUVBL1-RUVBL2 ATPase activity and by modulating the conformation and interactions of the PIH1D1 and RPAP3 components of R2TP. Taken together, our results show how TTT couples the recruitment of TOR to R2TP with the regulation of this chaperone system.
History
DepositionMay 19, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 6, 2021Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / database_2 / em_admin / pdbx_contact_author / pdbx_database_proc / pdbx_seq_map_depositor_info
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_seq_map_depositor_info.one_letter_code_mod

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Structure visualization

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Assembly

Deposited unit
A: RuvB-like 1
B: RuvB-like 2
C: RuvB-like 1
D: RuvB-like 2
E: RuvB-like 1
F: RuvB-like 2
H: TELO2-interacting protein 1 homolog,TELO2-interacting protein 1 homolog,TTI1
J: TELO2-interacting protein 2,TELO2-interacting protein 2,TTI2
K: Telomere length regulation protein TEL2 homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)632,59614
Polymers630,4609
Non-polymers2,1365
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 7 molecules ACEBDFK

#1: Protein RuvB-like 1 / 49 kDa TATA box-binding protein-interacting protein / 49 kDa TBP-interacting protein / 54 kDa ...49 kDa TATA box-binding protein-interacting protein / 49 kDa TBP-interacting protein / 54 kDa erythrocyte cytosolic protein / ECP-54 / INO80 complex subunit H / Nuclear matrix protein 238 / NMP 238 / Pontin 52 / TIP49a / TIP60-associated protein 54-alpha / TAP54-alpha


Mass: 50296.914 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: ADP / Source: (gene. exp.) Homo sapiens (human) / Gene: RUVBL1, INO80H, NMP238, TIP49, TIP49A / Plasmid: pCDF duet1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9Y265, DNA helicase
#2: Protein RuvB-like 2 / 48 kDa TATA box-binding protein-interacting protein / 48 kDa TBP-interacting protein / 51 kDa ...48 kDa TATA box-binding protein-interacting protein / 48 kDa TBP-interacting protein / 51 kDa erythrocyte cytosolic protein / ECP-51 / INO80 complex subunit J / Repressing pontin 52 / Reptin 52 / TIP49b / TIP60-associated protein 54-beta / TAP54-beta


Mass: 51222.465 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: ADP / Source: (gene. exp.) Homo sapiens (human) / Gene: RUVBL2, INO80J, TIP48, TIP49B, CGI-46 / Plasmid: pCDF duet / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9Y230, DNA helicase
#5: Protein Telomere length regulation protein TEL2 homolog / Protein clk-2 homolog / hCLK2


Mass: 53424.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: LGEMEPPALPREKEEFASAHF / Source: (gene. exp.) Homo sapiens (human) / Gene: TELO2, KIAA0683, TELO2 / Plasmid: pFastbac
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q9Y4R8

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TELO2-interacting protein ... , 2 types, 2 molecules HJ

#3: Protein TELO2-interacting protein 1 homolog,TELO2-interacting protein 1 homolog,TTI1 / Protein SMG10


Mass: 176844.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTI1, KIAA0406, SMG10 / Plasmid: pFastbac
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: O43156
#4: Protein TELO2-interacting protein 2,TELO2-interacting protein 2,TTI2


Mass: 95633.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTI2, C8orf41 / Plasmid: pFastbac
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q6NXR4

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Non-polymers , 1 types, 5 molecules

#6: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM

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Details

Has ligand of interestY

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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: TELO2-TTI1-TTI2-RUVBL1-RUVBL2 complex / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.58 MDa / Experimental value: YES
Buffer solutionpH: 7.5 / Details: Solutions were made fresh for protein purification
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM2-[4-(2-Hydroxyethyl)-1-piperazinyl]-ethanesulfonic acidHEPES1
2140 mMSodium ChrorideNaCl1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: LEICA PLUNGER / Cryogen name: ETHANE-PROPANE / Humidity: 90 % / Chamber temperature: 287.15 K / Details: 3sec

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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 / Nominal magnification: 130000 X / Nominal defocus min: 1200 nm / Calibrated defocus max: 3000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: BASIC
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 100 K / Temperature (min): 90 K
Image recordingAverage exposure time: 9 sec. / Electron dose: 60.17 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 10 / Num. of real images: 6000
Image scansSampling size: 5 µm / Width: 1034 / Height: 1034 / Movie frames/image: 40 / Used frames/image: 1-40

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Processing

EM software
IDNameVersionCategoryDetails
2RELION3.1image acquisitionRelion
4RELION3.1CTF correctionCTFFIND
7UCSF Chimera1.15model fittingUCSF Chimera
9PHENIX1.14model refinementPHENIX
10RELION3.1initial Euler assignmentRELION
11RELION3.1final Euler assignmentRELION
12RELION3.1classificationRELION
13RELION3.13D reconstructionRELION
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1000
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 267149 / Algorithm: BACK PROJECTION / Num. of class averages: 200 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL
Atomic model buildingPDB-ID: 6FO1

6fo1

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