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Specificity of the BRISC deubiquitinating enzyme is not due to selective binding to Lys63-linked polyubiquitin.

BRISC (Brcc36-containing isopeptidase complex) is a four-subunit deubiquitinating (DUB) enzyme that has a catalytic subunit, called Brcc36, that is a member of the JAMM/MPN(+) family of zinc metalloproteases. A notable feature of BRISC is its high specificity for cleaving Lys(63)-linked polyubiquitin. Here, we show that BRISC selectivity is not due to preferential binding to Lys(63)-linked polyubiquitin but is instead dictated by how the substrate isopeptide linkage is oriented within the enzyme active site. BRISC possesses a high affinity binding site for the ubiquitin hydrophobic surface patch that accounts for the bulk of the affinity between enzyme and substrate. Although BRISC can interact with either subunit of a diubiquitin conjugate, substrate cleavage occurs only when BRISC is bound to the hydrophobic patch of the distal (i.e. the "S1") ubiquitin at a ubiquitin-ubiquitin cleavage site. The importance of the Lys(63)-linked proximal (S1') ubiquitin was underscored by our finding that BRISC could not cleave the isopeptide bond joining a ubiquitin to a non-ubiquitin substrate. Finally, we also show that Abro1, another BRISC subunit, binds directly to Brcc36 and that the Brcc36-Abro1 heterodimer includes a minimal complex with Lys(63)-specific DUB activity.

Pubmed ID: 20032457


  • Cooper EM
  • Boeke JD
  • Cohen RE


The Journal of biological chemistry

Publication Data

April 2, 2010

Associated Grants

  • Agency: NCRR NIH HHS, Id: RR020839

Mesh Terms

  • Binding Sites
  • Carbon-Nitrogen Lyases
  • Catalytic Domain
  • HeLa Cells
  • Humans
  • Lysine
  • Membrane Proteins
  • Multiprotein Complexes
  • Polyubiquitin
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Recombinant Proteins
  • Substrate Specificity
  • Trans-Activators
  • Ubiquitination
  • Ubiquitins