Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases

Wang, Ping; Doxtader, Katelyn A.; Nam, Yunsun

doi:10.1016/j.molcel.2016.05.041

Title: Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases

Abstract

N⁶-methyladenosine (m⁶A) is a prevalent, reversible chemical modification of functional RNAs and is important for central events in biology. The core m₆A writers are Mettl3 and Mettl14, which both contain methyltransferase domains. How Mettl3 and Mettl14 cooperate to catalyze methylation of adenosines has remained elusive. Here, we present crystal structures of the complex of Mettl3/Mettl14 methyltransferase domains in apo form as well as with bound S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) in the catalytic site. We determine that the heterodimeric complex of methyltransferase domains, combined with CCCH motifs, constitutes the minimally required regions for creating m⁶A modifications in vitro. We also show that Mettl3 is the catalytically active subunit, while Mettl14 plays a structural role critical for substrate recognition. Our model provides a molecular explanation for why certain mutations of Mettl3 and Mettl14 lead to impaired function of the methyltransferase complex.

Authors:: Wang, Ping; Doxtader, Katelyn A.; Nam, Yunsun

Publication Date:: Thu Jun 30 00:00:00 EDT 2016

Research Org.:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: USDOE Office of Science (SC); Southwestern Medical Foundation; National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); Welch Foundation; Cancer Prevention and Research Institute of Texas (CPRIT); American Cancer Society; Harold C. Simmons Comprehensive Cancer Center

OSTI Identifier:: 1393677

Alternate Identifier(s):: OSTI ID: 1274763

Grant/Contract Number:: 2T32GM008297; I-1851; R1221; ACS-IRG-02-196; AC02-06CH11357

Resource Type:: Published Article

Journal Name:: Molecular Cell

Additional Journal Information:: Journal Name: Molecular Cell Journal Volume: 63 Journal Issue: 2; Journal ID: ISSN 1097-2765

Publisher:: Cell Press - Elsevier

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats


                    Wang, Ping, Doxtader, Katelyn A., and Nam, Yunsun. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases.  United States: N. p., 2016. 
Web.  doi:10.1016/j.molcel.2016.05.041.

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                    Wang, Ping, Doxtader, Katelyn A., & Nam, Yunsun. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases.  United States.  https://doi.org/10.1016/j.molcel.2016.05.041

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                    Wang, Ping, Doxtader, Katelyn A., and Nam, Yunsun. Thu .  
"Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases".  United States.  https://doi.org/10.1016/j.molcel.2016.05.041.

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@article{osti_1393677,

  title        = {Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases},

  author       = {Wang, Ping and Doxtader, Katelyn A. and Nam, Yunsun},

  abstractNote = {N6-methyladenosine (m6A) is a prevalent, reversible chemical modification of functional RNAs and is important for central events in biology. The core m6A writers are Mettl3 and Mettl14, which both contain methyltransferase domains. How Mettl3 and Mettl14 cooperate to catalyze methylation of adenosines has remained elusive. Here, we present crystal structures of the complex of Mettl3/Mettl14 methyltransferase domains in apo form as well as with bound S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) in the catalytic site. We determine that the heterodimeric complex of methyltransferase domains, combined with CCCH motifs, constitutes the minimally required regions for creating m6A modifications in vitro. We also show that Mettl3 is the catalytically active subunit, while Mettl14 plays a structural role critical for substrate recognition. Our model provides a molecular explanation for why certain mutations of Mettl3 and Mettl14 lead to impaired function of the methyltransferase complex.},

  doi          = {10.1016/j.molcel.2016.05.041},

  journal      = {Molecular Cell},

  number       = 2,

  volume       = 63,

  place        = {United States},

  year         = {Thu Jun 30 00:00:00 EDT 2016},

  month        = {Thu Jun 30 00:00:00 EDT 2016}

}

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Title: Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases

Abstract

Citation Formats

Multiple modes of RNA recognition by zinc finger proteins journal, June 2005

Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification journal, December 2015

N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO journal, October 2011

Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase journal, January 2014

Crystal Structure of the Nosiheptide-Resistance Methyltransferase of Streptomyces actuosus journal, August 2010

Gene expression regulation mediated through reversible m6A RNA methylation journal, March 2014

A Radioactivity-Based Assay for Screening Human m 6 A-RNA Methyltransferase, METTL3-METTL14 Complex, and Demethylase ALKBH5 journal, March 2016

RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock journal, November 2013

A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation journal, December 2013

N6-Adenosine methylation in mRNA: Substrate specificity and enzyme complexity journal, January 1994

Structure-Based Mechanistic Insights into DNMT1-Mediated Maintenance DNA Methylation journal, February 2012

N6-methyladenosine-dependent regulation of messenger RNA stability journal, November 2013

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes journal, July 2006

N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions journal, February 2015

m 6 A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation journal, January 2015

Coot model-building tools for molecular graphics journal, November 2004

LncRNAs: key players and novel insights into cervical cancer journal, December 2015

ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility journal, January 2013

Collaboration gets the most out of software journal, September 2013

N6-Methyladenosine Modification in a Long Noncoding RNA Hairpin Predisposes Its Conformation to Protein Binding journal, February 2016

Sequence specificity of the human mRNA N6-adenosine methylase in vitro journal, January 1990

Protein production by auto-induction in high-density shaking cultures journal, May 2005

N6-methyladenosine marks primary microRNAs for processing journal, March 2015

Sequence specificity of mRNA N6-adenosine methyltransferase journal, November 1990

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal, January 2010

PROCHECK: a program to check the stereochemical quality of protein structures journal, April 1993

RNA-binding proteins: modular design for efficient function journal, June 2007

The dynamic epitranscriptome: N6-methyladenosine and gene expression control journal, April 2014

Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5′ Sites journal, July 2014

m6A RNA Methylation Is Regulated by MicroRNAs and Promotes Reprogramming to Pluripotency journal, March 2015

Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation journal, August 2007

N6-methyladenosine–encoded epitranscriptomics journal, February 2016

Preparation of Human Nuclear RNA m6A Methyltransferases and Demethylases and Biochemical Characterization of Their Catalytic Activity book, January 2015

Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons journal, June 2012

N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells journal, January 2014

COSMIC: exploring the world's knowledge of somatic mutations in human cancer journal, October 2014

LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions journal, January 1995

Comparison of methylated sequences in messenger RNA and heterogeneous nuclear RNA from mouse L cells journal, October 1977

Structural basis for S -adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1 journal, June 2013

Novel genetic targets in endometrial cancer journal, April 2014

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq journal, April 2012

Structures of Liganded and Unliganded Rsr I N 6-Adenine DNA Methyltransferase : A DISTINCT ORIENTATION FOR ACTIVE COFACTOR BINDING journal, May 2003

FTO: linking m6A demethylation to adipogenesis journal, December 2014

N6-methyladenosine Modulates Messenger RNA Translation Efficiency journal, June 2015

Zinc finger proteins: getting a grip on RNA journal, February 2005

Structure Prediction and Phylogenetic Analysis of a Functionally Diverse Family of Proteins Homologous to the MT-A70 Subunit of the Human mRNA:m6A Methyltransferase journal, October 2002

Multiple modes of RNA recognition by zinc finger proteins
journal, June 2005

Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification
journal, December 2015

N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO
journal, October 2011

Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase
journal, January 2014

Crystal Structure of the Nosiheptide-Resistance Methyltransferase of Streptomyces actuosus
journal, August 2010

Gene expression regulation mediated through reversible m6A RNA methylation
journal, March 2014

A Radioactivity-Based Assay for Screening Human m 6 A-RNA Methyltransferase, METTL3-METTL14 Complex, and Demethylase ALKBH5
journal, March 2016

RNA-Methylation-Dependent RNA Processing Controls the Speed of the Circadian Clock
journal, November 2013

A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation
journal, December 2013

N6-Adenosine methylation in mRNA: Substrate specificity and enzyme complexity
journal, January 1994

Structure-Based Mechanistic Insights into DNMT1-Mediated Maintenance DNA Methylation
journal, February 2012

N6-methyladenosine-dependent regulation of messenger RNA stability
journal, November 2013

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes
journal, July 2006

N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions
journal, February 2015

m ⁶ A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation
journal, January 2015

Coot model-building tools for molecular graphics
journal, November 2004

LncRNAs: key players and novel insights into cervical cancer
journal, December 2015

ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility
journal, January 2013

Collaboration gets the most out of software
journal, September 2013

N6-Methyladenosine Modification in a Long Noncoding RNA Hairpin Predisposes Its Conformation to Protein Binding
journal, February 2016

Sequence specificity of the human mRNA N6-adenosine methylase in vitro
journal, January 1990

Protein production by auto-induction in high-density shaking cultures
journal, May 2005

N6-methyladenosine marks primary microRNAs for processing
journal, March 2015

Sequence specificity of mRNA N6-adenosine methyltransferase
journal, November 1990

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

PROCHECK: a program to check the stereochemical quality of protein structures
journal, April 1993

RNA-binding proteins: modular design for efficient function
journal, June 2007

The dynamic epitranscriptome: N6-methyladenosine and gene expression control
journal, April 2014

Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5′ Sites
journal, July 2014

m6A RNA Methylation Is Regulated by MicroRNAs and Promotes Reprogramming to Pluripotency
journal, March 2015

Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation
journal, August 2007

N6-methyladenosine–encoded epitranscriptomics
journal, February 2016

Preparation of Human Nuclear RNA m6A Methyltransferases and Demethylases and Biochemical Characterization of Their Catalytic Activity
book, January 2015

Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons
journal, June 2012

N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells
journal, January 2014

COSMIC: exploring the world's knowledge of somatic mutations in human cancer
journal, October 2014

LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions
journal, January 1995

Comparison of methylated sequences in messenger RNA and heterogeneous nuclear RNA from mouse L cells
journal, October 1977

Structural basis for S -adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1
journal, June 2013

Novel genetic targets in endometrial cancer
journal, April 2014

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq
journal, April 2012

Structures of Liganded and Unliganded Rsr I N 6-Adenine DNA Methyltransferase : A DISTINCT ORIENTATION FOR ACTIVE COFACTOR BINDING
journal, May 2003

FTO: linking m6A demethylation to adipogenesis
journal, December 2014

N6-methyladenosine Modulates Messenger RNA Translation Efficiency
journal, June 2015

Zinc finger proteins: getting a grip on RNA
journal, February 2005

Structure Prediction and Phylogenetic Analysis of a Functionally Diverse Family of Proteins Homologous to the MT-A70 Subunit of the Human mRNA:m6A Methyltransferase
journal, October 2002