Molecular architecture of human Polycomb repressive complex 2

Department of Molecular and Cell Biology , University of California , Berkeley , United States.
eLife Sciences (Impact Factor: 9.32). 10/2012; 1:e00005. DOI: 10.7554/eLife.00005
Source: PubMed

ABSTRACT Polycomb Repressive Complex 2 (PRC2) is essential for gene silencing, establishing transcriptional repression of specific genes by tri-methylating Lysine 27 of histone H3, a process mediated by cofactors such as AEBP2. In spite of its biological importance, little is known about PRC2 architecture and subunit organization. Here, we present the first three-dimensional electron microscopy structure of the human PRC2 complex bound to its cofactor AEBP2. Using a novel internal protein tagging-method, in combination with isotopic chemical cross-linking and mass spectrometry, we have localized all the PRC2 subunits and their functional domains and generated a detailed map of interactions. The position and stabilization effect of AEBP2 suggests an allosteric role of this cofactor in regulating gene silencing. Regions in PRC2 that interact with modified histone tails are localized near the methyltransferase site, suggesting a molecular mechanism for the chromatin-based regulation of PRC2 activity. DOI:

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Available from: Gabriel C Lander, Sep 28, 2015
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    • "Two structural features distinguish our EZH2 structure from catalytically competent conformations of other SET domain methyltransferases: the post-SET domain projects away from its expected position (Figure 3A), resulting in an incomplete cofactor binding site, and the I-SET domain is shifted towards the post-SET domain, which closes the histone binding groove and blocks the entrance of the substrate lysine channel (Figure 2 and Figure S10). While these features may be related to crystal lattice contacts which are numerous both at the post-SET and I-SET domains, there is evidence that at least some of the atypical features of our crystallized conformation (inactive trajectory of the post-SET) may be populated in the PRC2 complex in solution (Figure 3C) [53]. "
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    • "Clearly, further structural and mechanistic advances are needed to define how these remarkably conserved partner inputs control the efficiency of PRC2 output. Importantly, the recent report of EM-derived PRC2 architecture (Ciferri et al., 2012) provides the first full structural framework for analyzing PRC2 inner workings. This multilobed structure places portions of EED and SU(Z)12 in close proximity to the EZH2 SET domain—prime locations to impact PRC2 enzymatic function. "
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