McGinty Robert K, Henrici Ryan C, Tan Song
Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
1] Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] Schreyer Honors College, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Nature. 2014 Oct 30;514(7524):591-6. doi: 10.1038/nature13890.
The Polycomb group of epigenetic enzymes represses expression of developmentally regulated genes in many eukaryotes. This group includes the Polycomb repressive complex 1 (PRC1), which ubiquitylates nucleosomal histone H2A Lys 119 using its E3 ubiquitin ligase subunits, Ring1B and Bmi1, together with an E2 ubiquitin-conjugating enzyme, UbcH5c. However, the molecular mechanism of nucleosome substrate recognition by PRC1 or other chromatin enzymes is unclear. Here we present the crystal structure of the human Ring1B-Bmi1-UbcH5c E3-E2 complex (the PRC1 ubiquitylation module) bound to its nucleosome core particle substrate. The structure shows how a chromatin enzyme achieves substrate specificity by interacting with several nucleosome surfaces spatially distinct from the site of catalysis. Our structure further reveals an unexpected role for the ubiquitin E2 enzyme in substrate recognition, and provides insight into how the related histone H2A E3 ligase, BRCA1, interacts with and ubiquitylates the nucleosome.
多梳蛋白组表观遗传酶在许多真核生物中抑制发育调控基因的表达。该蛋白组包括多梳抑制复合物1（PRC1），它利用其E3泛素连接酶亚基Ring1B和Bmi1以及E2泛素结合酶UbcH5c，将核小体组蛋白H2A赖氨酸119泛素化。然而，PRC1或其他染色质酶识别核小体底物的分子机制尚不清楚。在此，我们展示了与核小体核心颗粒底物结合的人源Ring1B - Bmi1 - UbcH5c E3 - E2复合物（PRC1泛素化模块）的晶体结构。该结构展示了一种染色质酶如何通过与几个在空间上与催化位点不同的核小体表面相互作用来实现底物特异性。我们的结构进一步揭示了泛素E2酶在底物识别中的意外作用，并深入了解了相关组蛋白H2A E3连接酶BRCA1如何与核小体相互作用并使其泛素化。
