Polycomb repressive complex 2 in an autoinhibited state

Bratkowski, Matthew; Yang, Xin; Liu, Xin

doi:10.1074/jbc.m117.787572

Title: Polycomb repressive complex 2 in an autoinhibited state

Journal Article · Mon Jun 12 00:00:00 EDT 2017 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.m117.787572· OSTI ID:1376260

Bratkowski, Matthew ^[1]; Yang, Xin ^[1]; Liu, Xin ^[1]

UT Southwestern Medical Center, Dallas, TX (United States). Cecil H. and Ida Green Center for Reproductive Biology Sciences. Division of Basic Research. Dept. of Obstetrics and Gynecology. Dept. of Biophysics

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.

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

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357; AC02-05CH11231; AC02-76SF00515

OSTI ID:: 1376260

Journal Information:: Journal of Biological Chemistry, Vol. 292, Issue 32; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 11 works

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Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma Lee, Chul-Hwan; Yu, Jia-Ray; Granat, Jeffrey Genes & Development, Vol. 33, Issue 19-20 https://doi.org/10.1101/gad.328773.119	journal	September 2019
An Evolutionarily Conserved Structural Platform for PRC2 Inhibition by a Class of Ezh2 Inhibitors Bratkowski, Matthew; Yang, Xin; Liu, Xin Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-27175-w	journal	June 2018

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