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K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1.

An unusual deubiquitinating (DUB) activity exists in HeLa cell extracts that is highly specific for cleaving K63-linked but not K48-linked polyubiquitin chains. The activity is insensitive to both N-ethyl-maleimide and ubiquitin aldehyde, indicating that it lacks an active site cysteine residue, and gel filtration experiments show that it resides in a high molecular weight (approximately 600 kDa) complex. Using a biochemical approach, we found that the K63-specific DUB activity co-fractionated through seven chromatographic steps with three multisubunit complexes: the 19S (PA700) portion of the 26S proteasome, the COP9 signalosome (CSN) and a novel complex that includes the JAMM/MPN+ domain-containing protein Brcc36. When we analysed the individual complexes, we found that the activity was intrinsic to PA700 and the Brcc36 isopeptidase complex (BRISC), but that the CSN-associated activity was due entirely to an interaction with Brcc36. None of the complexes cleave K6, K11, K29, K48 or alpha-linked polyubiquitin, but they do cleave K63 linkages within mixed-linkage chains. Our results suggest that specificity for K63-linked polyubiquitin is a common property of the JAMM/MPN+ family of DUBs.

Pubmed ID: 19214193


  • Cooper EM
  • Cutcliffe C
  • Kristiansen TZ
  • Pandey A
  • Pickart CM
  • Cohen RE


The EMBO journal

Publication Data

March 18, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 5F32GM075712
  • Agency: NCRR NIH HHS, Id: RR020839

Mesh Terms

  • Cell Extracts
  • Ethylmaleimide
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysine
  • Membrane Proteins
  • Multiprotein Complexes
  • Peptide Hydrolases
  • Phenanthrolines
  • Polyubiquitin
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Substrate Specificity
  • Trans-Activators
  • Ubiquitination