5hyn | pdb_00005hyn
Structure of Human Polycomb Repressive Complex 2 (PRC2) with oncogenic histone H3K27M peptide
Structural highlights
FunctionJARD2_HUMAN Regulator of histone methyltransferase complexes that plays an essential role in embryonic development, including heart and liver development, neural tube fusion process and hematopoiesis. Acts by modulating histone methyltransferase activity and promoting the recruitment of histone methyltransferase complexes to their target genes. Binds DNA and mediates the recruitment of the PRC2 complex to target genes in embryonic stem cells. Does not have histone demethylase activity but regulates activity of various histone methyltransferase complexes. In embryonic stem cells, it associates with the PRC2 complex and inhibits trimethylation of 'Lys-27' of histone H3 (H3K27me3) by the PRC2 complex, thereby playing a key role in differentiation of embryonic stem cells and normal development. In cardiac cells, it is required to repress expression of cyclin-D1 (CCND1) by activating methylation of 'Lys-9' of histone H3 (H3K9me) by the GLP1/EHMT1 and G9a/EHMT2 histone methyltransferases. Also acts as a transcriptional repressor of ANF via its interaction with GATA4 and NKX2-5. Participates in the negative regulation of cell proliferation signaling.[1] Publication Abstract from PubMedPolycomb repressive complex 2 (PRC2) silences gene expression through trimethylation of K27 of histone H3 (H3K27me3) via its catalytic SET domain. A missense mutation in the substrate of PRC2, histone H3K27M, is associated with certain pediatric brain cancers and is linked to a global decrease of H3K27me3 in the affected cells thought to be mediated by inhibition of PRC2 activity. We present here the crystal structure of human PRC2 in complex with the inhibitory H3K27M peptide bound to the active site of the SET domain, with the methionine residue located in the pocket that normally accommodates the target lysine residue. The structure and binding studies suggest a mechanism for the oncogenic inhibition of H3K27M. The structure also reveals how binding of repressive marks, like H3K27me3, to the EED subunit of the complex leads to enhancement of the catalytic efficiency of the SET domain and thus the propagation of this repressive histone modification. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2.,Justin N, Zhang Y, Tarricone C, Martin SR, Chen S, Underwood E, De Marco V, Haire LF, Walker PA, Reinberg D, Wilson JR, Gamblin SJ Nat Commun. 2016 Apr 28;7:11316. doi: 10.1038/ncomms11316. PMID:27121947[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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