E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages.
An E3 ubiquitin ligase mediates the transfer of activated ubiquitin from an E2 ubiquitin-conjugating enzyme to its substrate lysine residues. Using a structure-based, yeast two-hybrid strategy, we discovered six previously unidentified interactions between the human heterodimeric RING E3 BRCA1-BARD1 and the human E2s UbcH6, Ube2e2, UbcM2, Ubc13, Ube2k and Ube2w. ... All six E2s bind directly to the BRCA1 RING motif and are active with BRCA1-BARD1 for autoubiquitination in vitro. Four of the E2s direct monoubiquitination of BRCA1. Ubc13-Mms2 and Ube2k direct the synthesis of Lys63- or Lys48-linked ubiquitin chains on BRCA1 and require an acceptor ubiquitin attached to BRCA1. Differences between the mono- and polyubiquitination activities of the BRCA1-interacting E2s correlate with their ability to bind ubiquitin noncovalently at a site distal to the active site. Thus, BRCA1 has the ability to direct the synthesis of specific polyubiquitin chain linkages, depending on the E2 bound to its RING.
Mesh Terms:
Amino Acid Sequence, BRCA1 Protein, Humans, Models, Molecular, Molecular Sequence Data, Polyubiquitin, Protein Structure, Quaternary, RING Finger Domains, Recombinant Fusion Proteins, Sequence Alignment, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases
Amino Acid Sequence, BRCA1 Protein, Humans, Models, Molecular, Molecular Sequence Data, Polyubiquitin, Protein Structure, Quaternary, RING Finger Domains, Recombinant Fusion Proteins, Sequence Alignment, Tumor Suppressor Proteins, Two-Hybrid System Techniques, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases
Nat. Struct. Mol. Biol.
Date: Oct. 01, 2007
PubMed ID: 17873885
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