Cryo-EM structure of substrate-bound human telomerase holoenzyme

Nguyen, Thi Hoang Duong; Tam, Jane; Wu, Robert A.; Greber, Basil J.; Toso, Daniel; Nogales, Eva; Collins, Kathleen

doi:10.1038/s41586-018-0062-x

Title: Cryo-EM structure of substrate-bound human telomerase holoenzyme

Abstract

Telomerase adds telomeric repeats to chromosome ends to balance incomplete replication. Telomerase regulation is implicated in cancer, aging and other human diseases, but progress towards telomerase clinical manipulation is hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of substrate-bound human telomerase holoenzyme at subnanometer resolution, describing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein-RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics

Authors:

Nguyen, Thi Hoang Duong ^[1]; Tam, Jane ^[2]; Wu, Robert A. ^[3]; Greber, Basil J. ^[1]; Toso, Daniel ^[2]; Nogales, Eva ^[1]; Collins, Kathleen ^[2]

Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States); Harvard Medical School, Boston, MA (United States)

Publication Date:: Wed Apr 25 00:00:00 EDT 2018

Research Org.:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC)

OSTI Identifier:: 1492320

Grant/Contract Number:: AC02-05CH11231

Resource Type:: Accepted Manuscript

Journal Name:: Nature (London)

Additional Journal Information:: Journal Name: Nature (London); Journal Volume: 557; Journal Issue: 7704; Journal ID: ISSN 0028-0836

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Nguyen, Thi Hoang Duong, Tam, Jane, Wu, Robert A., Greber, Basil J., Toso, Daniel, Nogales, Eva, and Collins, Kathleen. Cryo-EM structure of substrate-bound human telomerase holoenzyme.  United States: N. p., 2018. 
Web.  doi:10.1038/s41586-018-0062-x.

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                    Nguyen, Thi Hoang Duong, Tam, Jane, Wu, Robert A., Greber, Basil J., Toso, Daniel, Nogales, Eva, & Collins, Kathleen. Cryo-EM structure of substrate-bound human telomerase holoenzyme.  United States.  https://doi.org/10.1038/s41586-018-0062-x

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                    Nguyen, Thi Hoang Duong, Tam, Jane, Wu, Robert A., Greber, Basil J., Toso, Daniel, Nogales, Eva, and Collins, Kathleen. Wed .  
"Cryo-EM structure of substrate-bound human telomerase holoenzyme".  United States.  https://doi.org/10.1038/s41586-018-0062-x.  https://www.osti.gov/servlets/purl/1492320.

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@article{osti_1492320,

  title        = {Cryo-EM structure of substrate-bound human telomerase holoenzyme},

  author       = {Nguyen, Thi Hoang Duong and Tam, Jane and Wu, Robert A. and Greber, Basil J. and Toso, Daniel and Nogales, Eva and Collins, Kathleen},

  abstractNote = {Telomerase adds telomeric repeats to chromosome ends to balance incomplete replication. Telomerase regulation is implicated in cancer, aging and other human diseases, but progress towards telomerase clinical manipulation is hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of substrate-bound human telomerase holoenzyme at subnanometer resolution, describing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein-RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics},

  doi          = {10.1038/s41586-018-0062-x},

  journal      = {Nature (London)},

  number       = 7704,

  volume       = 557,

  place        = {United States},

  year         = {Wed Apr 25 00:00:00 EDT 2018},

  month        = {Wed Apr 25 00:00:00 EDT 2018}

}

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Telomerase is a ribonucleoprotein complex essential for maintenance of telomere DNA at linear chromosome ends. The catalytic core of Tetrahymena telomerase comprises a ternary complex of telomerase RNA (TER), telomerase reverse transcriptase (TERT), and the essential La family protein p65. NMR and crystal structures of p65 C-terminal domain and its complex with stem IV of TER reveal that RNA recognition is achieved by a combination of single- and double-stranded RNA binding, which induces a 105{sup o} bend in TER. The domain is a cryptic, atypical RNA recognition motif with a disordered C-terminal extension that forms an {alpha} helix in themore »« less
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Similar Records

Title: Cryo-EM structure of substrate-bound human telomerase holoenzyme

Abstract

Citation Formats

Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions journal, October 2015

Structure and function in rhodopsin: High-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line journal, October 2002

Complex interactions between the DNA-damage response and mammalian telomeres journal, November 2015

Protein Composition of Catalytically Active Human Telomerase from Immortal Cells journal, March 2007

RNA-protein binding interface in the telomerase ribonucleoprotein journal, November 2011

Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2 journal, November 2016

Molecular basis of telomere dysfunction in human genetic diseases journal, November 2015

A structure of the COPI coat and the role of coat proteins in membrane vesicle assembly journal, July 2015

Distinct Biogenesis Pathways for Human Telomerase RNA and H/ACA Small Nucleolar RNAs journal, May 2003

Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo journal, March 2010

High-level and high-throughput recombinant protein production by transient transfection of suspension-growing human 293-EBNA1 cells journal, January 2002

A Single Templating RNA in Yeast Telomerase journal, July 2015

Secondary Structure of Vertebrate Telomerase RNA journal, March 2000

DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy journal, May 2009

Prevention of overfitting in cryo-EM structure determination journal, July 2012

Role of Telomeres and Telomerase in Aging and Cancer journal, March 2016

Appion: An integrated, database-driven pipeline to facilitate EM image processing journal, April 2009

A critical stem-loop structure in the CR4-CR5 domain of mammalian telomerase RNA journal, January 2002

Automated molecular microscopy: The new Leginon system journal, July 2005

Crystal structure of an H/ACA box ribonucleoprotein particle journal, August 2006

The Phyre2 web portal for protein modeling, prediction and analysis journal, May 2015

Telomeropathies: An emerging spectrum disorder journal, May 2014

Human Telomerase RNA Accumulation in Cajal Bodies Facilitates Telomerase Recruitment to Telomeres and Telomere Elongation journal, September 2007

Solution Structure and Dynamics of the Wild-type Pseudoknot of Human Telomerase RNA journal, December 2008

Specific association of human telomerase activity with immortal cells and cancer journal, December 1994

The Role of Double-Strand Break Repair Pathways at Functional and Dysfunctional Telomeres journal, September 2014

An Enhanced H/ACA RNP Assembly Mechanism for Human Telomerase RNA journal, April 2012

The architecture of the spliceosomal U4/U6.U5 tri-snRNP journal, June 2015

The Box H/ACA Ribonucleoprotein Complex: Interplay of RNA and Protein Structures in Post-transcriptional RNA Modification journal, November 2009

Structural basis of template-boundary definition in Tetrahymena telomerase journal, October 2015

Structure of active dimeric human telomerase journal, March 2013

MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy journal, February 2017

Human telomerase specialization for repeat synthesis by unique handling of primer-template duplex journal, March 2014

Image processing for electron microscopy single-particle analysis using XMIPP journal, May 2008

Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation journal, August 2014

Structural basis for protein-RNA recognition in telomerase journal, May 2014

Gctf: Real-time CTF determination and correction journal, January 2016

Structural conservation in the template/pseudoknot domain of vertebrate telomerase RNA from teleost fish to human journal, August 2016

Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase journal, February 2006

Dynamic association and localization of human H/ACA RNP proteins journal, October 2006

Structure and folding of the Tetrahymena telomerase RNA pseudoknot journal, November 2016

Optimal Determination of Particle Orientation, Absolute Hand, and Contrast Loss in Single-particle Electron Cryomicroscopy journal, October 2003

Human Telomerase Domain Interactions Capture DNA for TEN Domain-Dependent Processive Elongation journal, May 2011

Purification of Human Telomerase Complexes Identifies Factors Involved in Telomerase Biogenesis and Telomere Length Regulation journal, December 2007

The genomics of inherited bone marrow failure: from mechanism to the clinic journal, February 2017

Structural and Functional Characterization of Human Telomerase RNA Processing and Cajal Body Localization Signals journal, September 2007

EMAN2: An extensible image processing suite for electron microscopy journal, January 2007

A Human Telomerase Holoenzyme Protein Required for Cajal Body Localization and Telomere Synthesis journal, January 2009

Visualizing density maps with UCSF Chimera journal, January 2007

Deciphering key features in protein structures with the new ENDscript server journal, April 2014

Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA journal, March 2010

Architecture of human telomerase RNA journal, August 2011

RELION: Implementation of a Bayesian approach to cryo-EM structure determination journal, December 2012

The architecture of Tetrahymena telomerase holoenzyme journal, April 2013

Structure and function of the N-terminal domain of the yeast telomerase reverse transcriptase journal, December 2017

Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies journal, August 2016

Semi-automated selection of cryo-EM particles in RELION-1.3 journal, February 2015

Telomere end-replication problem and cell aging journal, June 1992

Telomerase Mechanism of Telomere Synthesis journal, June 2017

RNA-guided isomerization of uridine to pseudouridine—pseudouridylation journal, December 2014

Telomerase: An RNP Enzyme Synthesizes DNA journal, July 2010

Focus: The interface between data collection and data processing in cryo-EM journal, May 2017

Progress in Human and Tetrahymena Telomerase Structure Determination journal, May 2017

Evolutionary perspectives of telomerase RNA structure and function journal, June 2016

Structure of the Tribolium castaneum telomerase catalytic subunit TERT journal, August 2008

Automated electron microscope tomography using robust prediction of specimen movements journal, October 2005

Human telomerase contains two cooperating telomerase RNA molecules journal, July 2001

Human Telomerase Activation Requires Two Independent Interactions between Telomerase RNA and Telomerase Reverse Transcriptase journal, August 2000

An Improved Cryogen for Plunge Freezing journal, September 2008

A Conserved WD40 Protein Binds the Cajal Body Localization Signal of scaRNP Particles journal, April 2009

Sampling the conformational space of the catalytic subunit of human γ-secretase journal, December 2015

Single-molecule analysis of human telomerase monomer journal, April 2008

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome journal, December 2019

Cryo-EM structure of the respiratory syncytial virus RNA polymerase journal, January 2020

Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen journal, February 2020

Red light-induced structure changes in phytochrome A from Pisum sativum journal, February 2021

Below 3 Å structure of apoferritin using a multipurpose TEM with a side entry cryoholder journal, April 2021

Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions
journal, October 2015

Structure and function in rhodopsin: High-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line
journal, October 2002

Complex interactions between the DNA-damage response and mammalian telomeres
journal, November 2015

Protein Composition of Catalytically Active Human Telomerase from Immortal Cells
journal, March 2007

RNA-protein binding interface in the telomerase ribonucleoprotein
journal, November 2011

Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2
journal, November 2016

Molecular basis of telomere dysfunction in human genetic diseases
journal, November 2015

A structure of the COPI coat and the role of coat proteins in membrane vesicle assembly
journal, July 2015

Distinct Biogenesis Pathways for Human Telomerase RNA and H/ACA Small Nucleolar RNAs
journal, May 2003

Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo
journal, March 2010

High-level and high-throughput recombinant protein production by transient transfection of suspension-growing human 293-EBNA1 cells
journal, January 2002

A Single Templating RNA in Yeast Telomerase
journal, July 2015

Secondary Structure of Vertebrate Telomerase RNA
journal, March 2000

DoG Picker and TiltPicker: Software tools to facilitate particle selection in single particle electron microscopy
journal, May 2009

Prevention of overfitting in cryo-EM structure determination
journal, July 2012

Role of Telomeres and Telomerase in Aging and Cancer
journal, March 2016

Appion: An integrated, database-driven pipeline to facilitate EM image processing
journal, April 2009

A critical stem-loop structure in the CR4-CR5 domain of mammalian telomerase RNA
journal, January 2002

Automated molecular microscopy: The new Leginon system
journal, July 2005

Crystal structure of an H/ACA box ribonucleoprotein particle
journal, August 2006

The Phyre2 web portal for protein modeling, prediction and analysis
journal, May 2015

Telomeropathies: An emerging spectrum disorder
journal, May 2014

Human Telomerase RNA Accumulation in Cajal Bodies Facilitates Telomerase Recruitment to Telomeres and Telomere Elongation
journal, September 2007

Solution Structure and Dynamics of the Wild-type Pseudoknot of Human Telomerase RNA
journal, December 2008

Specific association of human telomerase activity with immortal cells and cancer
journal, December 1994

The Role of Double-Strand Break Repair Pathways at Functional and Dysfunctional Telomeres
journal, September 2014

An Enhanced H/ACA RNP Assembly Mechanism for Human Telomerase RNA
journal, April 2012

The architecture of the spliceosomal U4/U6.U5 tri-snRNP
journal, June 2015

The Box H/ACA Ribonucleoprotein Complex: Interplay of RNA and Protein Structures in Post-transcriptional RNA Modification
journal, November 2009

Structural basis of template-boundary definition in Tetrahymena telomerase
journal, October 2015

Structure of active dimeric human telomerase
journal, March 2013

MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy
journal, February 2017

Human telomerase specialization for repeat synthesis by unique handling of primer-template duplex
journal, March 2014

Image processing for electron microscopy single-particle analysis using XMIPP
journal, May 2008

Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation
journal, August 2014

Structural basis for protein-RNA recognition in telomerase
journal, May 2014

Gctf: Real-time CTF determination and correction
journal, January 2016

Structural conservation in the template/pseudoknot domain of vertebrate telomerase RNA from teleost fish to human
journal, August 2016

Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase
journal, February 2006

Dynamic association and localization of human H/ACA RNP proteins
journal, October 2006

Structure and folding of the Tetrahymena telomerase RNA pseudoknot
journal, November 2016

Optimal Determination of Particle Orientation, Absolute Hand, and Contrast Loss in Single-particle Electron Cryomicroscopy
journal, October 2003

Human Telomerase Domain Interactions Capture DNA for TEN Domain-Dependent Processive Elongation
journal, May 2011

Purification of Human Telomerase Complexes Identifies Factors Involved in Telomerase Biogenesis and Telomere Length Regulation
journal, December 2007

The genomics of inherited bone marrow failure: from mechanism to the clinic
journal, February 2017

Structural and Functional Characterization of Human Telomerase RNA Processing and Cajal Body Localization Signals
journal, September 2007

EMAN2: An extensible image processing suite for electron microscopy
journal, January 2007

A Human Telomerase Holoenzyme Protein Required for Cajal Body Localization and Telomere Synthesis
journal, January 2009

Visualizing density maps with UCSF Chimera
journal, January 2007

Deciphering key features in protein structures with the new ENDscript server
journal, April 2014

Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA
journal, March 2010

Architecture of human telomerase RNA
journal, August 2011

RELION: Implementation of a Bayesian approach to cryo-EM structure determination
journal, December 2012

The architecture of Tetrahymena telomerase holoenzyme
journal, April 2013

Structure and function of the N-terminal domain of the yeast telomerase reverse transcriptase
journal, December 2017

Minimized human telomerase maintains telomeres and resolves endogenous roles of H/ACA proteins, TCAB1, and Cajal bodies
journal, August 2016

Semi-automated selection of cryo-EM particles in RELION-1.3
journal, February 2015

Telomere end-replication problem and cell aging
journal, June 1992

Telomerase Mechanism of Telomere Synthesis
journal, June 2017

RNA-guided isomerization of uridine to pseudouridine—pseudouridylation
journal, December 2014

Telomerase: An RNP Enzyme Synthesizes DNA
journal, July 2010

Focus: The interface between data collection and data processing in cryo-EM
journal, May 2017

Progress in Human and Tetrahymena Telomerase Structure Determination
journal, May 2017

Evolutionary perspectives of telomerase RNA structure and function
journal, June 2016

Structure of the Tribolium castaneum telomerase catalytic subunit TERT
journal, August 2008

Automated electron microscope tomography using robust prediction of specimen movements
journal, October 2005

Human telomerase contains two cooperating telomerase RNA molecules
journal, July 2001

Human Telomerase Activation Requires Two Independent Interactions between Telomerase RNA and Telomerase Reverse Transcriptase
journal, August 2000

An Improved Cryogen for Plunge Freezing
journal, September 2008

A Conserved WD40 Protein Binds the Cajal Body Localization Signal of scaRNP Particles
journal, April 2009

Sampling the conformational space of the catalytic subunit of human γ-secretase
journal, December 2015

Single-molecule analysis of human telomerase monomer
journal, April 2008

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019

Cryo-EM structure of the respiratory syncytial virus RNA polymerase
journal, January 2020

Preclinical Development of a Fusion Peptide Conjugate as an HIV Vaccine Immunogen
journal, February 2020

Red light-induced structure changes in phytochrome A from Pisum sativum
journal, February 2021

Below 3 Å structure of apoferritin using a multipurpose TEM with a side entry cryoholder
journal, April 2021

Structure and function of the N-terminal domain of the yeast telomerase reverse transcriptase
text, January 2018

Structural conservation in the template/pseudoknot domain of vertebrate telomerase RNA from teleost fish to human
text, January 2016

Human telomerase protein: Understanding how the catalytic activity is suppressed under single substitutions of some conserved residues. A computational study
journal, September 2018