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- PDB-7tre: Human telomerase catalytic core with shelterin protein TPP1 -

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Basic information

Entry
Database: PDB / ID: 7tre
TitleHuman telomerase catalytic core with shelterin protein TPP1
Components
  • Adrenocortical dysplasia protein homolog
  • Telomerase RNA, partial sequence
  • Telomerase reverse transcriptase
  • Telomeric repeat substrate
KeywordsREPLICATION / DNA / RNA
Function / homology
Function and homology information


positive regulation of single-stranded telomeric DNA binding / telomere assembly / positive regulation of hair cycle / template-free RNA nucleotidyltransferase / positive regulation of transdifferentiation / TERT-RMRP complex / DNA strand elongation / RNA-directed RNA polymerase complex / segmentation / telomerase catalytic core complex ...positive regulation of single-stranded telomeric DNA binding / telomere assembly / positive regulation of hair cycle / template-free RNA nucleotidyltransferase / positive regulation of transdifferentiation / TERT-RMRP complex / DNA strand elongation / RNA-directed RNA polymerase complex / segmentation / telomerase catalytic core complex / positive regulation of protein localization to nucleolus / urogenital system development / siRNA transcription / telomerase activity / protection from non-homologous end joining at telomere / Regulation of MITF-M-dependent genes involved in DNA damage repair and senescence / : / RNA-templated DNA biosynthetic process / establishment of protein localization to telomere / shelterin complex / Telomere C-strand synthesis initiation / telomere capping / Telomere C-strand (Lagging Strand) Synthesis / positive regulation of telomere maintenance / nuclear telomere cap complex / siRNA processing / Processive synthesis on the C-strand of the telomere / Polymerase switching on the C-strand of the telomere / Removal of the Flap Intermediate from the C-strand / telomerase RNA binding / telomerase holoenzyme complex / positive regulation of vascular associated smooth muscle cell migration / embryonic limb morphogenesis / protein localization to chromosome, telomeric region / DNA biosynthetic process / telomeric DNA binding / RNA-templated transcription / positive regulation of stem cell proliferation / mitochondrial nucleoid / : / negative regulation of cellular senescence / negative regulation of telomere maintenance via telomerase / positive regulation of Wnt signaling pathway / telomere maintenance via telomerase / Telomere Extension By Telomerase / replicative senescence / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of G1/S transition of mitotic cell cycle / negative regulation of endothelial cell apoptotic process / response to cadmium ion / DNA polymerase binding / Packaging Of Telomere Ends / positive regulation of vascular associated smooth muscle cell proliferation / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / positive regulation of telomere maintenance via telomerase / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / telomere maintenance / Meiotic synapsis / positive regulation of nitric-oxide synthase activity / skeletal system development / mitochondrion organization / positive regulation of D-glucose import / intracellular protein transport / Formation of the beta-catenin:TCF transactivating complex / regulation of protein stability / DNA Damage/Telomere Stress Induced Senescence / PML body / transcription coactivator binding / positive regulation of miRNA transcription / RNA-directed DNA polymerase / positive regulation of angiogenesis / RNA-directed DNA polymerase activity / positive regulation of protein binding / protein-folding chaperone binding / cellular response to hypoxia / negative regulation of neuron apoptotic process / tRNA binding / chromosome, telomeric region / nuclear body / nuclear speck / negative regulation of gene expression / RNA-dependent RNA polymerase activity / protein-containing complex binding / nucleolus / protein homodimerization activity / DNA binding / RNA binding / nucleoplasm / identical protein binding / nucleus / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Shelterin complex subunit TPP1/Est3 / Shelterin complex subunit, TPP1/ACD / Adrenocortical dysplasia protein / : / Telomerase reverse transcriptase, C-terminal extension / Telomerase ribonucleoprotein complex - RNA binding domain / Telomerase reverse transcriptase / Telomerase ribonucleoprotein complex - RNA-binding domain / Telomerase ribonucleoprotein complex - RNA binding domain / Reverse transcriptase domain ...Shelterin complex subunit TPP1/Est3 / Shelterin complex subunit, TPP1/ACD / Adrenocortical dysplasia protein / : / Telomerase reverse transcriptase, C-terminal extension / Telomerase ribonucleoprotein complex - RNA binding domain / Telomerase reverse transcriptase / Telomerase ribonucleoprotein complex - RNA-binding domain / Telomerase ribonucleoprotein complex - RNA binding domain / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
: / DNA / DNA (> 10) / RNA / RNA (> 10) / RNA (> 100) / Telomerase reverse transcriptase / Adrenocortical dysplasia protein homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLiu, B. / He, Y. / Wang, Y. / Song, H. / Zhou, Z.H. / Feigon, J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM131901 United States
National Science Foundation (NSF, United States)MCB2016540 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM071940 United States
CitationJournal: Nature / Year: 2022
Title: Structure of active human telomerase with telomere shelterin protein TPP1.
Authors: Baocheng Liu / Yao He / Yaqiang Wang / He Song / Z Hong Zhou / Juli Feigon /
Abstract: Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG. Its activity is a determinant of cancer ...Human telomerase is a RNA-protein complex that extends the 3' end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG. Its activity is a determinant of cancer progression, stem cell renewal and cellular aging. Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP1. Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein. Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN-TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling-including the TEN domain and the TRAP-thumb helix channel-are largely structurally homologous to those in Tetrahymena telomerase, and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR1532 overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies are located at the TERT-TER and TEN-TRAP-TPP1 interfaces, highlighting the importance of TER-TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets.
History
DepositionJan 28, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2022Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 4, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Telomerase RNA, partial sequence
A: Telomerase reverse transcriptase
D: Telomeric repeat substrate
C: Adrenocortical dysplasia protein homolog


Theoretical massNumber of molelcules
Total (without water)299,3764
Polymers299,3764
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: RNA chain Telomerase RNA, partial sequence


Mass: 145477.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: GenBank: 1932797
#2: Protein Telomerase reverse transcriptase / HEST2 / Telomerase catalytic subunit / Telomerase-associated protein 2 / TP2


Mass: 130711.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TERT, EST2, TCS1, TRT / Production host: Homo sapiens (human) / References: UniProt: O14746, RNA-directed DNA polymerase
#3: DNA chain Telomeric repeat substrate


Mass: 5514.567 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#4: Protein Adrenocortical dysplasia protein homolog / POT1 and TIN2-interacting protein


Mass: 17672.637 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACD, PIP1, PTOP, TINT1, TPP1 / Production host: Homo sapiens (human) / References: UniProt: Q96AP0

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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: active human telomerase RNP with shelterin protein TPP1
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 4000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118845 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00614084
ELECTRON MICROSCOPYf_angle_d0.73720143
ELECTRON MICROSCOPYf_dihedral_angle_d23.2123839
ELECTRON MICROSCOPYf_chiral_restr0.0422454
ELECTRON MICROSCOPYf_plane_restr0.0051756

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