title: BMI1-RING1B is an autoinhibited RING E3 ubiquitin ligase.
abstract: Polycomb repressive complex 1 (PRC1) is required for ubiquitination of histone H2A lysine 119, an epigenetic mark associated with repression of genes important in developmental regulation. The E3 ligase activity of PRC1 resides in the RING1A/B subunit when paired with one of six PCGF partners. The best known of these is the oncogene BMI1/PCGF4. We find that canonical PRC1 E3 ligases such as PCGF4-RING1B have intrinsically very low enzymatic activity compared with non-canonical PRC1 RING dimers. The structure of a high-activity variant in complex with E2 (PCGF5-RING1B-UbcH5c) reveals only subtle differences from an earlier PCGF4 complex structure. However, two charged residues present in the modelled interface with E2-conjugated ubiquitin prove critical: in BMI1/PCGF4, these residues form a salt bridge that may limit efficient ubiquitin transfer. The intrinsically low activity of the PCGF4-RING1B heterodimer is offset by a relatively favourable interaction with nucleosome substrates, resulting in an efficient site-specific monoubiquitination.
authors.affiliation: Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Asad M
authors.initials: AM
authors.lastname: Taherbhoy
authors.affiliation: Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Huang
authors.affiliation: Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Cochran
mesh_terms: D004926:Escherichia coli / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D044763:Ubiquitin-Conjugating Enzymes; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human; D044767:Ubiquitin-Protein Ligases; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7