Crystal structure of the PRC1 ubiquitylation module bound to the nucleosome

• Published in: Nature (London) Vol. 514; no. 7524; pp. 591 - 596
• Main Authors: McGinty, Robert K., Henrici, Ryan C., Tan, Song
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.10.2014; Nature Publishing Group
• Subjects: 631/337; 631/337/100/101; 631/535/1266; 82/16; 82/29; 82/80; 82/83; Analysis; Catalysis; Chromatin; Coordination compounds; Crystal structure; Crystallography, X-Ray; Crystals; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - metabolism; Enzymes; Epigenetic inheritance; Histones - chemistry; Histones - metabolism; Humanities and Social Sciences; Humans; Identification and classification; Ligases; Methods; Models, Molecular; multidisciplinary; Nucleosomes; Nucleosomes - chemistry; Nucleosomes - metabolism; Polycomb Repressive Complex 1 - chemistry; Polycomb Repressive Complex 1 - metabolism; Polypeptides; Protein research; Proteins; Science; Structure; Substrates; Ubiquitin; Ubiquitin-Conjugating Enzymes - chemistry; Ubiquitin-Conjugating Enzymes - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; United States
• ISSN: 0028-0836; 1476-4687
• 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. The crystal structure of the PRC1 ubiquitylation module bound to its nucleosome core substrate is determined, revealing how a histone-modifying enzyme achieves substrate specificity by recognizing nucleosome surfaces distinct from the site of catalysis, and uncovering a unique role for the ubiquitin E2 enzyme in substrate recognition. PRC1 ubiquitylation module structure Polycomb group proteins repress the expression of developmentally regulated genes in higher eukaryotes. Polycomb repressive complex 1 (PRC1) ubiquitylates histone H2A using E3 ubiquitin ligase subunits, Ring1B and Bmi1, together with an E2 ubiquitin-conjugating enzyme, UbcH5c. Here, Song Tan and colleagues describe the crystal structure of the PRC1 ubiquitylation module bound to its nucleosome core substrate. The structure shows how a histone modifying enzyme achieves substrate specificity by interacting with multiple nucleosome surfaces spatially distinct from the site of catalysis, and reveals an unexpected role for the E2 enzyme in substrate recognition. Based on their new data, the authors generate a model for nucleosome binding of the related BRCA1 H2A E3 ligase that can be used to examine the role of BRCA1's histone-modifying activity in development and cancer predisposition.