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.
Highlights
Polycomb-group proteins control many fundamental biological processes, such as anatomical development in mammals and vernalization in plants
We determined the crystal structure of an apo-Polycomb repressive complex 2 (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
The previously solved crystal structures of ctPRC2 provided a wealth of insight into the catalytic mechanism of this enzyme complex [8]
Summary
Polycomb-group proteins control many fundamental biological processes, such as anatomical development in mammals and vernalization in plants. 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. Ezh is inactive without Eed and Suz12 [4] In lower eukaryotes such as fungi, PRC2-like complexes have been found to mediate H3K27 methylation as well [5,6,7,8]. Disruption of the autoinhibited conformation results in overactivated ctPRC2 caused by increased histone substrate binding as shown by steady-state enzyme kinetics studies of the wild-type and a gain-of-function mutant ctPRC2. The autoinhibition may set a threshold for the enzyme complex to sense the effective concentration of the histone substrate but may serve as a structural foundation for enzyme activation by some cellular mechanisms
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