Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase

Jean François Couture; Evys Collazo; Patricia A. Ortiz-Tello; Joseph S. Brunzelle; Raymond C. Trievel

doi:10.1038/nsmb1273

Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase

Jean François Couture, Evys Collazo, Patricia A. Ortiz-Tello, Joseph S. Brunzelle, Raymond C. Trievel^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

239 Scopus citations

Abstract

JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated ε-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH⋯O) hydrogen bonds that position one of the ζ-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.

Original language	English (US)
Pages (from-to)	689-695
Number of pages	7
Journal	Nature Structural and Molecular Biology
Volume	14
Issue number	8
DOIs	https://doi.org/10.1038/nsmb1273
State	Published - Aug 2007

Funding

We? thank? D.? Engelke? for? reading? the? manuscript? and? furnishing? useful? comments,? P.J.? O’Brien? for? advice? regarding? protein? expression? and? J.? Leykam? at? the? Michigan? State? University? Macromolecular? Structure,? Sequencing? and? Synthesis? Facility? for? his? assistance? with? amino? acid? analysis.? Use? of? the? Advanced? Photon? Source? was? supported? by? the? US? Department? of? Energy,? Basic? Energy? Sciences,? Office? of? Science,? under? contract? no.? W-31-109-ENG-38.? The? GM/CA? CAT? has? been? funded? in? whole? or? in? part? with? Federal? funds? from? the? National? Cancer? Institute? (Y1-CO-1020)? and? the? National? Institute? of? General? Medical? Science? (Y1-GM-1104)? of? the? US? National? Institutes? of? Health? (NIH),? and? we? thank? R.? Sanishvili,? D.? Yoder? and? S.? Corcoran? for? their? assistance? with? data? collection? at? beamline? ID-23.? Use? of? the? University? of? Michigan? DNA? Sequencing? Core? was? supported? by? the? NIH? through? the? University? of? Michigan’s? Cancer? Center? Support? Grant? (5? P30? CA46592).? J.-F.C.? is? a? Canadian? Institutes? of? Health? Sciences? postdoctoral? fellow.? This? work? was? supported? by? grants? from? the? University? of? Michigan’s? Office? of? the? Vice? President? for? Research? and? from? the? NIH? (GM073839)? to? R.C.T.

ASJC Scopus subject areas

Molecular Biology
Structural Biology

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10.1038/nsmb1273

Cite this

@article{17990a5f6918413687adf49b281d394d,

title = "Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase",

abstract = "JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated ε-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH⋯O) hydrogen bonds that position one of the ζ-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.",

author = "Couture, {Jean Fran{\c c}ois} and Evys Collazo and Ortiz-Tello, {Patricia A.} and Brunzelle, {Joseph S.} and Trievel, {Raymond C.}",

note = "Funding Information: We? thank? D.? Engelke? for? reading? the? manuscript? and? furnishing? useful? comments,? P.J.? O{\textquoteright}Brien? for? advice? regarding? protein? expression? and? J.? Leykam? at? the? Michigan? State? University? Macromolecular? Structure,? Sequencing? and? Synthesis? Facility? for? his? assistance? with? amino? acid? analysis.? Use? of? the? Advanced? Photon? Source? was? supported? by? the? US? Department? of? Energy,? Basic? Energy? Sciences,? Office? of? Science,? under? contract? no.? W-31-109-ENG-38.? The? GM/CA? CAT? has? been? funded? in? whole? or? in? part? with? Federal? funds? from? the? National? Cancer? Institute? (Y1-CO-1020)? and? the? National? Institute? of? General? Medical? Science? (Y1-GM-1104)? of? the? US? National? Institutes? of? Health? (NIH),? and? we? thank? R.? Sanishvili,? D.? Yoder? and? S.? Corcoran? for? their? assistance? with? data? collection? at? beamline? ID-23.? Use? of? the? University? of? Michigan? DNA? Sequencing? Core? was? supported? by? the? NIH? through? the? University? of? Michigan{\textquoteright}s? Cancer? Center? Support? Grant? (5? P30? CA46592).? J.-F.C.? is? a? Canadian? Institutes? of? Health? Sciences? postdoctoral? fellow.? This? work? was? supported? by? grants? from? the? University? of? Michigan{\textquoteright}s? Office? of? the? Vice? President? for? Research? and? from? the? NIH? (GM073839)? to? R.C.T.",

year = "2007",

month = aug,

doi = "10.1038/nsmb1273",

language = "English (US)",

volume = "14",

pages = "689--695",

journal = "Nature Structural and Molecular Biology",

issn = "1545-9993",

publisher = "Nature Publishing Group",

number = "8",

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T1 - Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase

AU - Couture, Jean François

AU - Collazo, Evys

AU - Ortiz-Tello, Patricia A.

AU - Brunzelle, Joseph S.

AU - Trievel, Raymond C.

N1 - Funding Information: We? thank? D.? Engelke? for? reading? the? manuscript? and? furnishing? useful? comments,? P.J.? O’Brien? for? advice? regarding? protein? expression? and? J.? Leykam? at? the? Michigan? State? University? Macromolecular? Structure,? Sequencing? and? Synthesis? Facility? for? his? assistance? with? amino? acid? analysis.? Use? of? the? Advanced? Photon? Source? was? supported? by? the? US? Department? of? Energy,? Basic? Energy? Sciences,? Office? of? Science,? under? contract? no.? W-31-109-ENG-38.? The? GM/CA? CAT? has? been? funded? in? whole? or? in? part? with? Federal? funds? from? the? National? Cancer? Institute? (Y1-CO-1020)? and? the? National? Institute? of? General? Medical? Science? (Y1-GM-1104)? of? the? US? National? Institutes? of? Health? (NIH),? and? we? thank? R.? Sanishvili,? D.? Yoder? and? S.? Corcoran? for? their? assistance? with? data? collection? at? beamline? ID-23.? Use? of? the? University? of? Michigan? DNA? Sequencing? Core? was? supported? by? the? NIH? through? the? University? of? Michigan’s? Cancer? Center? Support? Grant? (5? P30? CA46592).? J.-F.C.? is? a? Canadian? Institutes? of? Health? Sciences? postdoctoral? fellow.? This? work? was? supported? by? grants? from? the? University? of? Michigan’s? Office? of? the? Vice? President? for? Research? and? from? the? NIH? (GM073839)? to? R.C.T.

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N2 - JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated ε-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH⋯O) hydrogen bonds that position one of the ζ-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.

AB - JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated ε-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH⋯O) hydrogen bonds that position one of the ζ-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.

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Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase

Abstract

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ASJC Scopus subject areas

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Crystal structure of JMJD2A in ternary complex with an histone H3K9me3 peptide and 2-oxoglutarate

Crystal structure of JMJ2D2A in ternary complex with histone H3-K36me2 and succinate