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- EMDB-26086: Human telomerase catalytic core structure at 3.3 Angstrom -

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Basic information

Entry
Database: EMDB / ID: EMD-26086
TitleHuman telomerase catalytic core structure at 3.3 Angstrom
Map dataTelomerase catalytic core structure at 3.3 Angstrom
Sample
  • Complex: human telomerase catalytic core with DNA-substrate
    • RNA: Telomerase RNA, partial sequence
    • Protein or peptide: Telomerase reverse transcriptase
    • DNA: Telomeric repeat substrate
KeywordsDNA / RNA / REPLICATION
Function / homology
Function and homology information


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 / positive regulation of protein localization to nucleolus / siRNA transcription / telomerase activity ...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 / positive regulation of protein localization to nucleolus / siRNA transcription / telomerase activity / Regulation of MITF-M-dependent genes involved in DNA damage repair and senescence / : / RNA-templated DNA biosynthetic process / establishment of protein localization to telomere / nuclear telomere cap complex / siRNA processing / telomerase RNA binding / telomerase holoenzyme complex / positive regulation of vascular associated smooth muscle cell migration / DNA biosynthetic process / telomeric DNA binding / RNA-templated transcription / positive regulation of stem cell proliferation / mitochondrial nucleoid / negative regulation of cellular senescence / 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 / positive regulation of vascular associated smooth muscle cell proliferation / telomere maintenance / positive regulation of nitric-oxide synthase activity / mitochondrion organization / positive regulation of D-glucose import / Formation of the beta-catenin:TCF transactivating complex / regulation of protein stability / 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 speck / negative regulation of gene expression / RNA-dependent RNA polymerase activity / nucleolus / protein homodimerization activity / DNA binding / RNA binding / nucleoplasm / identical protein binding / nucleus / metal ion binding / plasma membrane / cytosol
Similarity search - Function
: / 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
Telomerase reverse transcriptase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 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_26086.png

Downloads & links

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Map

FileDownload / File: emd_26086.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTelomerase catalytic core structure at 3.3 Angstrom
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.06880306 - 0.14215542
Average (Standard dev.)0.00021361822 (±0.003477428)
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 : human telomerase catalytic core with DNA-substrate

EntireName: human telomerase catalytic core with DNA-substrate
Components
  • Complex: human telomerase catalytic core with DNA-substrate
    • RNA: Telomerase RNA, partial sequence
    • Protein or peptide: Telomerase reverse transcriptase
    • DNA: Telomeric repeat substrate

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Supramolecule #1: human telomerase catalytic core with DNA-substrate

SupramoleculeName: human telomerase catalytic core with DNA-substrate / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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 #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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 4.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

7521

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 291504
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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