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- EMDB-26088: Human telomerase catalytic core RNP with H2A/H2B -

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Basic information

Entry
Database: EMDB / ID: EMD-26088
TitleHuman telomerase catalytic core RNP with H2A/H2B
Map dataTelomerase catalytic core RNP structure with H2A/H2B
Sample
  • Complex: active human telomerase catalytic core with shelterin protein TPP1
    • Protein or peptide: Histone H2B type 1-C/E/F/G/I
    • Protein or peptide: Histone H2A
    • 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 / Replacement of protamines by nucleosomes in the male pronucleus / response to cadmium ion / 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 / Deposition of new CENPA-containing nucleosomes at the centromere / 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 / RNA Polymerase I Promoter Opening / Assembly of the ORC complex at the origin of replication / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / DNA methylation / Condensation of Prophase Chromosomes / SIRT1 negatively regulates rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / HCMV Late Events / positive regulation of nitric-oxide synthase activity / innate immune response in mucosa / PRC2 methylates histones and DNA / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / mitochondrion organization / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / positive regulation of D-glucose import / HDACs deacetylate histones / Nonhomologous End-Joining (NHEJ) / RNA Polymerase I Promoter Escape / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / regulation of protein stability / G2/M DNA damage checkpoint / B-WICH complex positively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / PML body / Meiotic recombination / transcription coactivator binding / Pre-NOTCH Transcription and Translation / positive regulation of miRNA transcription / RNA-directed DNA polymerase / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / positive regulation of angiogenesis / structural constituent of chromatin / RNA-directed DNA polymerase activity / antimicrobial humoral immune response mediated by antimicrobial peptide / nucleosome / positive regulation of protein binding / nucleosome assembly / E3 ubiquitin ligases ubiquitinate target proteins / antibacterial humoral response / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / protein-folding chaperone binding / RUNX1 regulates transcription of genes involved in differentiation of HSCs / HATs acetylate histones / Processing of DNA double-strand break ends / cellular response to hypoxia / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / Estrogen-dependent gene expression
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 / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site ...: / 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 / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Histone-fold / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Histone H2A / Telomerase reverse transcriptase / Histone H2B type 1-C/E/F/G/I
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 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_26088.png

Downloads & links

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Map

FileDownload / File: emd_26088.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTelomerase catalytic core RNP structure with H2A/H2B
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: 0.017
Minimum - Maximum-0.043562185 - 0.09394865
Average (Standard dev.)0.0002009022 (±0.0028329466)
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 catalytic core with shelterin protein TPP1

EntireName: active human telomerase catalytic core with shelterin protein TPP1
Components
  • Complex: active human telomerase catalytic core with shelterin protein TPP1
    • Protein or peptide: Histone H2B type 1-C/E/F/G/I
    • Protein or peptide: Histone H2A
    • RNA: Telomerase RNA, partial sequence
    • Protein or peptide: Telomerase reverse transcriptase
    • DNA: Telomeric repeat substrate

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Supramolecule #1: active human telomerase catalytic core with shelterin protein TPP1

SupramoleculeName: active human telomerase catalytic core with shelterin protein TPP1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Histone H2B type 1-C/E/F/G/I

MacromoleculeName: Histone H2B type 1-C/E/F/G/I / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.937213 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MPEPAKSAPA PKKGSKKAVT KAQKKDGKKR KRSRKESYSV YVYKVLKQVH PDTGISSKAM GIMNSFVNDI FERIAGEASR LAHYNKRST ITSREIQTAV RLLLPGELAK HAVSEGTKAV TKYTSSK

UniProtKB: Histone H2B type 1-C/E/F/G/I

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Macromolecule #2: Histone H2A

MacromoleculeName: Histone H2A / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.047451 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MSGRGKQGGK VRAKAKSRSS RAGLQFPVGR VHRLLRKGNY AERVGAGAPV YLAAVLEYLT AEILELAGNA ARDNKKTRII PRHLQLAIR NDEELNKLLG KVTIAQGGVL PNIQAVLLPK KTESQKTKSK

UniProtKB: Histone H2A

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Macromolecule #4: Telomerase reverse transcriptase

MacromoleculeName: Telomerase reverse transcriptase / type: protein_or_peptide / ID: 4 / 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: Telomerase RNA, partial sequence

MacromoleculeName: Telomerase RNA, partial sequence / type: rna / ID: 3 / 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 #5: Telomeric repeat substrate

MacromoleculeName: Telomeric repeat substrate / type: dna / ID: 5 / 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: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 83992
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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