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- EMDB-26087: Human telomerase catalytic core with shelterin protein TPP1 -

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Basic information

Entry
Database: EMDB / ID: EMD-26087
TitleHuman telomerase catalytic core with shelterin protein TPP1
Map dataTelomerase catalytic core structure with shelterin protein TPP1
Sample
  • Complex: active human telomerase RNP with shelterin protein TPP1
    • RNA: Telomerase RNA, partial sequenceTelomerase RNA component
    • Protein or peptide: Telomerase reverse transcriptase
    • DNA: Telomeric repeat substrate
    • Protein or peptide: Adrenocortical dysplasia protein homolog
KeywordsDNA / RNA / REPLICATION
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 / telomerase catalytic core complex / segmentation ...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 / telomerase catalytic core complex / segmentation / siRNA transcription / urogenital system development / positive regulation of protein localization to nucleolus / protection from non-homologous end joining at telomere / telomerase activity / telomerase RNA reverse transcriptase activity / RNA-templated DNA biosynthetic process / establishment of protein localization to telomere / shelterin complex / Telomere C-strand synthesis initiation / Telomere C-strand (Lagging Strand) Synthesis / nuclear telomere cap complex / siRNA processing / positive regulation of telomere maintenance / 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 / telomere capping / telomerase RNA binding / positive regulation of vascular associated smooth muscle cell migration / telomerase holoenzyme complex / embryonic limb morphogenesis / protein localization to chromosome, telomeric region / telomeric DNA binding / DNA biosynthetic process / RNA-templated transcription / positive regulation of stem cell proliferation / mitochondrial nucleoid / negative regulation of cellular senescence / negative regulation of telomere maintenance via telomerase / Telomere Extension By Telomerase / positive regulation of Wnt signaling pathway / telomere maintenance via telomerase / replicative senescence / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of G1/S transition of mitotic cell cycle / response to cadmium ion / negative regulation of endothelial cell apoptotic process / DNA polymerase binding / Packaging Of Telomere Ends / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / positive regulation of telomerase activity / positive regulation of vascular associated smooth muscle cell proliferation / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / Meiotic synapsis / positive regulation of telomere maintenance via telomerase / telomere maintenance / mitochondrion organization / skeletal system development / positive regulation of nitric-oxide synthase activity / positive regulation of glucose import / intracellular protein transport / Formation of the beta-catenin:TCF transactivating complex / regulation of protein stability / transcription coactivator binding / DNA Damage/Telomere Stress Induced Senescence / PML body / positive regulation of miRNA transcription / RNA-directed DNA polymerase / positive regulation of angiogenesis / RNA-directed DNA polymerase activity / positive regulation of protein binding / cellular response to hypoxia / protein-folding chaperone binding / negative regulation of neuron apoptotic process / tRNA binding / chromosome, telomeric region / nuclear body / nuclear speck / RNA-dependent RNA polymerase activity / negative regulation of gene expression / protein-containing complex binding / nucleolus / protein homodimerization activity / DNA binding / RNA binding / nucleoplasm / identical protein binding / metal ion binding / nucleus / 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 (RNA-dependent DNA polymerase) ...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 (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Telomerase reverse transcriptase / Adrenocortical dysplasia protein homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLiu B / He Y
Funding support United States, 3 items
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, 2022-
Header (metadata) releaseApr 20, 2022-
Map releaseApr 20, 2022-
UpdateFeb 21, 2024-
Current statusFeb 21, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26087.png

Downloads & links

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Map

FileDownload / File: emd_26087.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTelomerase catalytic core structure with shelterin protein TPP1
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.069142856 - 0.13645682
Average (Standard dev.)0.00020517666 (±0.003680461)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : active human telomerase RNP with shelterin protein TPP1

EntireName: active human telomerase RNP with shelterin protein TPP1
Components
  • Complex: active human telomerase RNP with shelterin protein TPP1
    • RNA: Telomerase RNA, partial sequenceTelomerase RNA component
    • Protein or peptide: Telomerase reverse transcriptase
    • DNA: Telomeric repeat substrate
    • Protein or peptide: Adrenocortical dysplasia protein homolog

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Supramolecule #1: active human telomerase RNP with shelterin protein TPP1

SupramoleculeName: active human telomerase RNP with shelterin protein TPP1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Telomerase RNA, partial sequence

MacromoleculeName: Telomerase RNA, partial sequence / type: rna / ID: 1 / Number of copies: 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 145.477797 KDa
SequenceString: GGGUUGCGGA GGGUGGGCCU GGGAGGGGUG GUGGCCAUUU UUUGUCUAAC CCUAACUGAG AAGGGCGUAG GCGCCGUGCU UUUGCUCCC CGCGCGCUGU UUUUCUCGCU GACUUUCAGC GGGCGGAAAA GCCUCGGCCU GCCGCCUUCC ACCGUUCAUU C UAGAGCAA ...String:
GGGUUGCGGA GGGUGGGCCU GGGAGGGGUG GUGGCCAUUU UUUGUCUAAC CCUAACUGAG AAGGGCGUAG GCGCCGUGCU UUUGCUCCC CGCGCGCUGU UUUUCUCGCU GACUUUCAGC GGGCGGAAAA GCCUCGGCCU GCCGCCUUCC ACCGUUCAUU C UAGAGCAA ACAAAAAAUG UCAGCUGCUG GCCCGUUCGC CCCUCCCGGG GACCUGCGGC GGGUCGCCUG CCCAGCCCCC GA ACCCCGC CUGGAGGCCG CGGUCGGCCC GGGGCUUCUC CGGAGGCACC CACUGCCACC GCGAAGAGUU GGGCUCUGUC AGC CGCGGG UCUCUCGGGG GCGAGGGCGA GGUUCAGGCC UUUCAGGCCG CAGGAAGAGG AACGGAGCGA GUCCCCGCGC GCGG CGCGA UUCCCUGAGC UGUGGGACGU GCACCCAGGA CUCGGCUCAC ACAUGC

GENBANK: GENBANK: U85256.1

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Macromolecule #2: Telomerase reverse transcriptase

MacromoleculeName: Telomerase reverse transcriptase / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: RNA-directed DNA polymerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 130.711492 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GHMSAWSHPQ FEKGGGSGGG SGGSAWSHPQ FEKSAMPRAP RCRAVRSLLR SHYREVLPLA TFVRRLGPQG WRLVQRGDPA AFRALVAQC LVCVPWDARP PPAAPSFRQV SCLKELVARV LQRLCERGAK NVLAFGFALL DGARGGPPEA FTTSVRSYLP N TVTDALRG ...String:
GHMSAWSHPQ FEKGGGSGGG SGGSAWSHPQ FEKSAMPRAP RCRAVRSLLR SHYREVLPLA TFVRRLGPQG WRLVQRGDPA AFRALVAQC LVCVPWDARP PPAAPSFRQV SCLKELVARV LQRLCERGAK NVLAFGFALL DGARGGPPEA FTTSVRSYLP N TVTDALRG SGAWGLLLRR VGDDVLVHLL ARCALFVLVA PSCAYQVCGP PLYQLGAATQ ARPPPHASGP RRRLGCERAW NH SVREAGV PLGLPAPGAR RRGGSASRSL PLPKRPRRGA APEPERTPVG QGSWAHPGRT RGPSDRGFCV VSPARPAEEA TSL EGALSG TRHSHPSVGR QHHAGPPSTS RPPRPWDTPC PPVYAETKHF LYSSGDKEQL RPSFLLSSLR PSLTGARRLV ETIF LGSRP WMPGTPRRLP RLPQRYWQMR PLFLELLGNH AQCPYGVLLK THCPLRAAVT PAAGVCAREK PQGSVAAPEE EDTDP RRLV QLLRQHSSPW QVYGFVRACL RRLVPPGLWG SRHNERRFLR NTKKFISLGK HAKLSLQELT WKMSVRDCAW LRRSPG VGC VPAAEHRLRE EILAKFLHWL MSVYVVELLR SFFYVTETTF QKNRLFFYRK SVWSKLQSIG IRQHLKRVQL RELSEAE VR QHREARPALL TSRLRFIPKP DGLRPIVNMD YVVGARTFRR EKRAERLTSR VKALFSVLNY ERARRPGLLG ASVLGLDD I HRAWRTFVLR VRAQDPPPEL YFVKVDVTGA YDTIPQDRLT EVIASIIKPQ NTYCVRRYAV VQKAAHGHVR KAFKSHVST LTDLQPYMRQ FVAHLQETSP LRDAVVIEQS SSLNEASSGL FDVFLRFMCH HAVRIRGKSY VQCQGIPQGS ILSTLLCSLC YGDMENKLF AGIRRDGLLL RLVDDFLLVT PHLTHAKTFL RTLVRGVPEY GCVVNLRKTV VNFPVEDEAL GGTAFVQMPA H GLFPWCGL LLDTRTLEVQ SDYSSYARTS IRASLTFNRG FKAGRNMRRK LFGVLRLKCH SLFLDLQVNS LQTVCTNIYK IL LLQAYRF HACVLQLPFH QQVWKNPTFF LRVISDTASL CYSILKAKNA GMSLGAKGAA GPLPSEAVQW LCHQAFLLKL TRH RVTYVP LLGSLRTAQT QLSRKLPGTT LTALEAAANP ALPSDFKTIL D

UniProtKB: Telomerase reverse transcriptase

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Macromolecule #4: Adrenocortical dysplasia protein homolog

MacromoleculeName: Adrenocortical dysplasia protein homolog / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.672637 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GAGSGRLVLR PWIRELILGS ETPSSPRAGQ LLEVLQDAEA AVAGPSHAPD TSDVGATLLV SDGTHSVRCL VTREALDTSD WEEKEFGFR GTEGRLLLLQ DCGVHVQVAE GGAPAEFYLQ VDRFSLLPTE QPRLRVPGCN QDLDVQKKLY DCLEEHLSES T SSN

UniProtKB: Adrenocortical dysplasia protein homolog

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Macromolecule #3: Telomeric repeat substrate

MacromoleculeName: Telomeric repeat substrate / type: dna / ID: 3 / Number of copies: 1 / Classification: DNA
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.514567 KDa
SequenceString:
(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT)(DT) (DT)(DT)(DT)(DT)(DA)(DG)(DG)(DG)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 4.0 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

7521

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 118845

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