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PMID: 26151332 Published · epublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S.

BMI1-RING1B is an autoinhibited RING E3 ubiquitin ligase.

Nature communications ·Vol. 6 ·2015-07-07 ·Pages 7621

Taherbhoy AM, Huang OW, Cochran AG

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.

MeSH Terms
Escherichia coli/metabolism Gene Expression Regulation, Enzymologic Humans Mitogen-Activated Protein Kinase 7/classification,genetics,metabolism Polycomb Repressive Complex 1/chemistry,classification,genetics,metabolism Ubiquitin-Conjugating Enzymes/genetics,metabolism Ubiquitin-Protein Ligases/genetics,metabolism
Chemicals
Ubiquitin-Conjugating Enzymes Polycomb Repressive Complex 1 RNF2 protein, human Ubiquitin-Protein Ligases MAPK7 protein, human Mitogen-Activated Protein Kinase 7
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Taherbhoy Asad M
Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Huang Oscar W
Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Cochran Andrea G
Department of Early Discovery Biochemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms8621
Published
2015-07-07
Epub
2015-00-07
Pages
7621
Language
English
Region
England
NLM ID
101528555
Subset
IM
Databases
PDB
4S3O
External Links
PubMed source DOI: 10.1038/ncomms8621 View journal details
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