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- PDB-7trc: Human telomerase H/ACA RNP at 3.3 Angstrom -

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Basic information

Entry
Database: PDB / ID: 7trc
TitleHuman telomerase H/ACA RNP at 3.3 Angstrom
Components
  • (H/ACA ribonucleoprotein complex subunit ...) x 4
  • Telomerase Cajal body protein 1
  • Telomerase RNA, partial sequenceTelomerase RNA component
KeywordsREPLICATION / DNA / RNA
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 telomere maintenance via telomerase / positive regulation of DNA repair / 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
: / RNA / RNA (> 10) / RNA (> 100) / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 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
K: Telomerase Cajal body protein 1
G: H/ACA ribonucleoprotein complex subunit DKC1
J: H/ACA ribonucleoprotein complex subunit 3
B: Telomerase RNA, partial sequence
H: H/ACA ribonucleoprotein complex subunit 1
I: H/ACA ribonucleoprotein complex subunit 2
D: H/ACA ribonucleoprotein complex subunit 1
F: H/ACA ribonucleoprotein complex subunit 3
E: H/ACA ribonucleoprotein complex subunit 2
C: H/ACA ribonucleoprotein complex subunit DKC1


Theoretical massNumber of molelcules
Total (without water)415,06110
Polymers415,06110
Non-polymers00
Water0
1


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

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Components

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H/ACA ribonucleoprotein complex subunit ... , 4 types, 8 molecules GCJFHDIE

#2: Protein H/ACA ribonucleoprotein complex subunit DKC1 / CBF5 homolog / Dyskerin / Nopp140-associated protein of 57 kDa / Nucleolar protein NAP57 / ...CBF5 homolog / Dyskerin / Nopp140-associated protein of 57 kDa / Nucleolar protein NAP57 / Nucleolar protein family A member 4 / snoRNP protein DKC1


Mass: 57779.211 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DKC1, NOLA4 / Production host: Homo sapiens (human)
References: UniProt: O60832, Isomerases; Intramolecular transferases; Transferring other groups
#3: Protein H/ACA ribonucleoprotein complex subunit 3 / Nucleolar protein 10 / Nucleolar protein family A member 3 / snoRNP protein NOP10


Mass: 7719.989 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NOP10, NOLA3 / Production host: Homo sapiens (human) / References: UniProt: Q9NPE3
#5: Protein H/ACA ribonucleoprotein complex subunit 1 / Nucleolar protein family A member 1 / snoRNP protein GAR1


Mass: 22387.963 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GAR1, NOLA1 / Production host: Homo sapiens (human) / References: UniProt: Q9NY12
#6: Protein H/ACA ribonucleoprotein complex subunit 2 / Nucleolar protein family A member 2 / snoRNP protein NHP2


Mass: 17226.070 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NHP2, NOLA2, HSPC286 / Production host: Homo sapiens (human) / References: UniProt: Q9NX24

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Protein / RNA chain , 2 types, 2 molecules KB

#1: Protein Telomerase Cajal body protein 1 / WD repeat-containing protein 79 / WD40 repeat-containing protein antisense to TP53 gene / WRAP53beta


Mass: 59357.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WRAP53, TCAB1, WDR79 / Production host: Homo sapiens (human) / References: UniProt: Q9BUR4
#4: RNA chain Telomerase RNA, partial sequence / Telomerase RNA component


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

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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: human telomerase H/ACA RNP / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
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 FIELDBright-field microscopy / 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: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 256859 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315319
ELECTRON MICROSCOPYf_angle_d0.58821146
ELECTRON MICROSCOPYf_dihedral_angle_d11.3892859
ELECTRON MICROSCOPYf_chiral_restr0.042428
ELECTRON MICROSCOPYf_plane_restr0.0052349

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