Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2017 Aug 11;29232:13323-13332. doi: 10.1074/jbc.M117.787572.
Show Gene links
Show Anatomy links
Polycomb repressive complex 2 in an autoinhibited state.
Bratkowski M
,
Yang X
,
Liu X
.
???displayArticle.abstract???
Polycomb-group proteins control many fundamental biological processes, such as anatomical development in mammals and vernalization in plants. Polycomb repressive complex 2 (PRC2) is responsible for methylation of histone H3 lysine 27 (H3K27), and trimethylated H3K27 (H3K27me3) is implicated in epigenetic gene silencing. Recent genomic, biochemical, and structural data indicate that PRC2 is broadly conserved from yeast to human in many aspects. Here, we determined the crystal structure of an apo-PRC2 from the fungus Chaetomium thermophilum captured in a bona fide autoinhibited state, which represents a novel conformation of PRC2 associated with enzyme regulation in light of the basal and stimulated states that we reported previously. We found that binding by the cofactor S-adenosylmethionine mitigates this autoinhibited structural state. Using steady-state enzyme kinetics, we also demonstrated that disrupting the autoinhibition results in a vastly activated enzyme complex. Autoinhibition provides a novel structural platform that may enable control of PRC2 activity in response to diverse transcriptional states and chromatin contexts and set a ground state to allow PRC2 activation by other cellular mechanisms as well.
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010, Pubmed
Adams,
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
2010,
Pubmed
Antonysamy,
Structural context of disease-associated mutations and putative mechanism of autoinhibition revealed by X-ray crystallographic analysis of the EZH2-SET domain.
2013,
Pubmed
Boriack-Sjodin,
Protein Methyltransferases: A Distinct, Diverse, and Dynamic Family of Enzymes.
2016,
Pubmed
Brooun,
Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.
2016,
Pubmed
Cao,
SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex.
2004,
Pubmed
Cifuentes-Rojas,
Regulatory interactions between RNA and polycomb repressive complex 2.
2014,
Pubmed
Connolly,
The Fusarium graminearum histone H3 K27 methyltransferase KMT6 regulates development and expression of secondary metabolite gene clusters.
2013,
Pubmed
Dumesic,
Product binding enforces the genomic specificity of a yeast polycomb repressive complex.
2015,
Pubmed
Hansen,
A model for transmission of the H3K27me3 epigenetic mark.
2008,
Pubmed
Horowitz,
Conservation and functional importance of carbon-oxygen hydrogen bonding in AdoMet-dependent methyltransferases.
2013,
Pubmed
Jamieson,
Regional control of histone H3 lysine 27 methylation in Neurospora.
2013,
Pubmed
Jamieson,
Loss of HP1 causes depletion of H3K27me3 from facultative heterochromatin and gain of H3K27me2 at constitutive heterochromatin.
2016,
Pubmed
Janke,
Metabolism and epigenetics.
2015,
Pubmed
Jiao,
Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2.
2015,
Pubmed
Justin,
Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.
2016,
Pubmed
Kaneko,
PRC2 binds active promoters and contacts nascent RNAs in embryonic stem cells.
2013,
Pubmed
Kaneko,
Nascent RNA interaction keeps PRC2 activity poised and in check.
2014,
Pubmed
Kim,
Targeting EZH2 in cancer.
2016,
Pubmed
Li,
Jarid2 and PRC2, partners in regulating gene expression.
2010,
Pubmed
Majer,
A687V EZH2 is a gain-of-function mutation found in lymphoma patients.
2012,
Pubmed
Margueron,
Role of the polycomb protein EED in the propagation of repressive histone marks.
2009,
Pubmed
McCabe,
Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27).
2012,
Pubmed
McCoy,
Phaser crystallographic software.
2007,
Pubmed
Murshudov,
Refinement of macromolecular structures by the maximum-likelihood method.
1997,
Pubmed
Otwinowski,
Processing of X-ray diffraction data collected in oscillation mode.
1997,
Pubmed
Pufall,
Autoinhibitory domains: modular effectors of cellular regulation.
2002,
Pubmed
Riising,
Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide.
2014,
Pubmed
Schmitges,
Histone methylation by PRC2 is inhibited by active chromatin marks.
2011,
Pubmed
Voigt,
Asymmetrically modified nucleosomes.
2012,
Pubmed
Whitcomb,
Polycomb Group proteins: an evolutionary perspective.
2007,
Pubmed
Winn,
Overview of the CCP4 suite and current developments.
2011,
Pubmed
Wu,
Structure of the catalytic domain of EZH2 reveals conformational plasticity in cofactor and substrate binding sites and explains oncogenic mutations.
2013,
Pubmed
