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- EMDB-26085: Human telomerase H/ACA RNP at 3.3 Angstrom -

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Basic information

Entry
Database: EMDB / ID: EMD-26085
TitleHuman telomerase H/ACA RNP at 3.3 Angstrom
Map dataH/ACA lobe of human telomerase
Sample
  • Complex: human telomerase H/ACA RNP
    • Protein or peptide: Telomerase Cajal body protein 1
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit DKC1
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit 3
    • RNA: Telomerase RNA, partial sequenceTelomerase RNA component
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit 1
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit 2
KeywordsDNA / RNA / REPLICATION
Function / homology
Function and homology information


telomere formation via telomerase / box H/ACA scaRNP complex / box H/ACA telomerase RNP complex / telomerase RNA localization to Cajal body / protein localization to Cajal body / Cajal body organization / snoRNA guided rRNA pseudouridine synthesis / box H/ACA snoRNP complex / rRNA pseudouridine synthesis / box H/ACA sno(s)RNA 3'-end processing ...telomere formation via telomerase / box H/ACA scaRNP complex / box H/ACA telomerase RNP complex / telomerase RNA localization to Cajal body / protein localization to Cajal body / Cajal body organization / snoRNA guided rRNA pseudouridine synthesis / box H/ACA snoRNP complex / rRNA pseudouridine synthesis / box H/ACA sno(s)RNA 3'-end processing / snRNA pseudouridine synthesis / Isomerases; Intramolecular transferases; Transferring other groups / mRNA pseudouridine synthesis / enzyme-directed rRNA pseudouridine synthesis / pseudouridine synthesis / telomerase RNA stabilization / telomerase activity / box H/ACA snoRNA binding / regulation of telomerase RNA localization to Cajal body / pseudouridine synthase activity / scaRNA localization to Cajal body / positive regulation of protein localization to Cajal body / positive regulation of establishment of protein localization to telomere / positive regulation of telomerase RNA localization to Cajal body / sno(s)RNA-containing ribonucleoprotein complex / telomerase RNA binding / telomerase holoenzyme complex / rRNA modification in the nucleus and cytosol / positive regulation of double-strand break repair / positive regulation of double-strand break repair via homologous recombination / positive regulation of double-strand break repair via nonhomologous end joining / Association of TriC/CCT with target proteins during biosynthesis / RNA folding / Telomere Extension By Telomerase / telomere maintenance via telomerase / Cajal body / RNA processing / maturation of LSU-rRNA / positive regulation of telomerase activity / positive regulation of DNA repair / positive regulation of telomere maintenance via telomerase / fibrillar center / rRNA processing / site of double-strand break / cytosolic large ribosomal subunit / histone binding / protein-folding chaperone binding / chromosome, telomeric region / nuclear body / DNA repair / ubiquitin protein ligase binding / protein-containing complex binding / nucleolus / RNA binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
H/ACA ribonucleoprotein complex, subunit Gar1/Naf1 / H/ACA RNP complex subunit Gar1/Naf1, Cbf5-binding domain / Gar1/Naf1 RNA binding region / tRNA pseudouridine synthase B family / Dyskerin-like / DKCLD (NUC011) domain / DKCLD (NUC011) domain / H/ACA ribonucleoprotein complex, subunit Nop10 / H/ACA ribonucleoprotein complex, subunit Nop10 superfamily / Nucleolar RNA-binding protein, Nop10p family ...H/ACA ribonucleoprotein complex, subunit Gar1/Naf1 / H/ACA RNP complex subunit Gar1/Naf1, Cbf5-binding domain / Gar1/Naf1 RNA binding region / tRNA pseudouridine synthase B family / Dyskerin-like / DKCLD (NUC011) domain / DKCLD (NUC011) domain / H/ACA ribonucleoprotein complex, subunit Nop10 / H/ACA ribonucleoprotein complex, subunit Nop10 superfamily / Nucleolar RNA-binding protein, Nop10p family / Pseudouridine synthase II, N-terminal / tRNA pseudouridylate synthase B, C-terminal / TruB family pseudouridylate synthase (N terminal domain) / tRNA pseudouridylate synthase B C-terminal domain / Uncharacterised domain CHP00451 / PUA domain / Pseudouridine synthase, catalytic domain superfamily / Putative RNA-binding Domain in PseudoUridine synthase and Archaeosine transglycosylase / PUA domain / PUA domain profile. / PUA domain superfamily / H/ACA ribonucleoprotein complex, subunit Nhp2-like / PUA-like superfamily / Ribosomal protein L7Ae/L8/Nhp2 family / Ribosomal protein L7Ae/L30e/S12e/Gadd45 / Ribosomal protein L7Ae/L30e/S12e/Gadd45 family / 50S ribosomal protein L30e-like / Translation protein, beta-barrel domain superfamily / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
H/ACA ribonucleoprotein complex subunit DKC1 / Telomerase Cajal body protein 1 / H/ACA ribonucleoprotein complex subunit 3 / H/ACA ribonucleoprotein complex subunit 2 / H/ACA ribonucleoprotein complex subunit 1
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_26085.png

Downloads & links

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Map

FileDownload / File: emd_26085.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationH/ACA lobe of human telomerase
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.025
Minimum - Maximum-0.11053562 - 0.18189988
Average (Standard dev.)0.0000026550704 (±0.0041175843)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 352.0 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 H/ACA RNP

EntireName: human telomerase H/ACA RNP
Components
  • Complex: human telomerase H/ACA RNP
    • Protein or peptide: Telomerase Cajal body protein 1
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit DKC1
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit 3
    • RNA: Telomerase RNA, partial sequenceTelomerase RNA component
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit 1
    • Protein or peptide: H/ACA ribonucleoprotein complex subunit 2

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Supramolecule #1: human telomerase H/ACA RNP

SupramoleculeName: human telomerase H/ACA RNP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Telomerase Cajal body protein 1

MacromoleculeName: Telomerase Cajal body protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.35707 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKTLETQPLA PDCCPSDQDP APAHPSPHAS PMNKNADSEL MPPPPERGDP PRLSPDPVAG SAVSQELREG DPVSLSTPLE TEFGSPSEL SPRIEEQELS ENTSLPAEEA NGSLSEEEAN GPELGSGKAM EDTSGEPAAE DEGDTAWNYS FSQLPRFLSG S WSEFSTQP ...String:
MKTLETQPLA PDCCPSDQDP APAHPSPHAS PMNKNADSEL MPPPPERGDP PRLSPDPVAG SAVSQELREG DPVSLSTPLE TEFGSPSEL SPRIEEQELS ENTSLPAEEA NGSLSEEEAN GPELGSGKAM EDTSGEPAAE DEGDTAWNYS FSQLPRFLSG S WSEFSTQP ENFLKGCKWA PDGSCILTNS ADNILRIYNL PPELYHEGEQ VEYAEMVPVL RMVEGDTIYD YCWYSLMSSA QP DTSYVAS SSRENPIHIW DAFTGELRAS FRAYNHLDEL TAAHSLCFSP DGSQLFCGFN RTVRVFSTAR PGRDCEVRAT FAK KQGQSG IISCIAFSPA QPLYACGSYG RSLGLYAWDD GSPLALLGGH QGGITHLCFH PDGNRFFSGA RKDAELLCWD LRQS GYPLW SLGREVTTNQ RIYFDLDPTG QFLVSGSTSG AVSVWDTDGP GNDGKPEPVL SFLPQKDCTN GVSLHPSLPL LATAS GQRV FPEPTESGDE GEELGLPLLS TRHVHLECRL QLWWCGGAPD SSIPDDHQGE KGQGGTEGGV GELI

UniProtKB: Telomerase Cajal body protein 1

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Macromolecule #2: H/ACA ribonucleoprotein complex subunit DKC1

MacromoleculeName: H/ACA ribonucleoprotein complex subunit DKC1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
EC number: Isomerases; Intramolecular transferases; Transferring other groups
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.779211 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADAEVIILP KKHKKKKERK SLPEEDVAEI QHAEEFLIKP ESKVAKLDTS QWPLLLKNFD KLNVRTTHYT PLACGSNPLK REIGDYIRT GFINLDKPSN PSSHEVVAWI RRILRVEKTG HSGTLDPKVT GCLIVCIERA TRLVKSQQSA GKEYVGIVRL H NAIEGGTQ ...String:
MADAEVIILP KKHKKKKERK SLPEEDVAEI QHAEEFLIKP ESKVAKLDTS QWPLLLKNFD KLNVRTTHYT PLACGSNPLK REIGDYIRT GFINLDKPSN PSSHEVVAWI RRILRVEKTG HSGTLDPKVT GCLIVCIERA TRLVKSQQSA GKEYVGIVRL H NAIEGGTQ LSRALETLTG ALFQRPPLIA AVKRQLRVRT IYESKMIEYD PERRLGIFWV SCEAGTYIRT LCVHLGLLLG VG GQMQELR RVRSGVMSEK DHMVTMHDVL DAQWLYDNHK DESYLRRVVY PLEKLLTSHK RLVMKDSAVN AICYGAKIML PGV LRYEDG IEVNQEIVVI TTKGEAICMA IALMTTAVIS TCDHGIVAKI KRVIMERDTY PRKWGLGPKA SQKKLMIKQG LLDK HGKPT DSTPATWKQE YVDYSESAKK EVVAEVVKAP QVVAEAAKTA KRKRESESES DETPPAAPQL IKKEKKKSKK DKKAK AGLE SGAEPGDGDS DTTKKKKKKK KAKEVELVSE

UniProtKB: H/ACA ribonucleoprotein complex subunit DKC1

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Macromolecule #3: H/ACA ribonucleoprotein complex subunit 3

MacromoleculeName: H/ACA ribonucleoprotein complex subunit 3 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.719989 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MFLQYYLNEQ GDRVYTLKKF DPMGQQTCSA HPARFSPDDK YSRHRITIKK RFKVLMTQQP RPVL

UniProtKB: H/ACA ribonucleoprotein complex subunit 3

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Macromolecule #5: H/ACA ribonucleoprotein complex subunit 1

MacromoleculeName: H/ACA ribonucleoprotein complex subunit 1 / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.387963 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSFRGGGRGG FNRGGGGGGF NRGGSSNHFR GGGGGGGGGN FRGGGRGGFG RGGGRGGFNK GQDQGPPERV VLLGEFLHPC EDDIVCKCT TDENKVPYFN APVYLENKEQ IGKVDEIFGQ LRDFYFSVKL SENMKASSFK KLQKFYIDPY KLLPLQRFLP R PPGEKGPP ...String:
MSFRGGGRGG FNRGGGGGGF NRGGSSNHFR GGGGGGGGGN FRGGGRGGFG RGGGRGGFNK GQDQGPPERV VLLGEFLHPC EDDIVCKCT TDENKVPYFN APVYLENKEQ IGKVDEIFGQ LRDFYFSVKL SENMKASSFK KLQKFYIDPY KLLPLQRFLP R PPGEKGPP RGGGRGGRGG GRGGGGRGGG RGGGFRGGRG GGGGGFRGGR GGGFRGRGH

UniProtKB: H/ACA ribonucleoprotein complex subunit 1

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Macromolecule #6: H/ACA ribonucleoprotein complex subunit 2

MacromoleculeName: H/ACA ribonucleoprotein complex subunit 2 / type: protein_or_peptide / ID: 6 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.22607 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MTKIKADPDG PEAQAEACSG ERTYQELLVN QNPIAQPLAS RRLTRKLYKC IKKAVKQKQI RRGVKEVQKF VNKGEKGIMV LAGDTLPIE VYCHLPVMCE DRNLPYVYIP SKTDLGAAAG SKRPTCVIMV KPHEEYQEAY DECLEEVQSL PLPL

UniProtKB: H/ACA ribonucleoprotein complex subunit 2

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Macromolecule #4: Telomerase RNA, partial sequence

MacromoleculeName: Telomerase RNA, partial sequence / type: rna / ID: 4 / 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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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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 256859

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