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Papers In Press, published online ahead of print March 24, 2005
JMUSDA HNRC, Tufts University, Boston, MA 02111
Corresponding Author: fu.shang{at}tufts.edu
Ubiquitin plays essential roles in various cellular processes and therefore it is of keen interest to study the structure-function relationship of ubiquitin itself. This study investigated the modification of K6 of ubiquitin and its physiological consequences. Mass spectrometry-based peptide mapping and N-terminal sequencing demonstrated that, among the 7 K residues in ubiquitin, K6 was the most readily labeled with sulfo-NHS-biotin. The K6-biotinylated ubiquitin was incorporated into high mass ubiquitin conjugates as efficiently as unmodified ubiquitin. However, K6-biotinylated ubiquitin inhibited ubiquitin-dependent proteolysis, as conjugates formed with K6-biotinylated ubiquitin were resistant to proteasomal degradation. Ubiquitins with a mutation of the K6 residue had similar phenotypes as K6-biotinylated ubiquitin. K6-mutated (K6A, K6R and K6W) ubiquitins also inhibited ATP-dependent proteolysis and caused accumulation of ubiquitin conjugates. Conjugates formed with K6W mutant ubiquitin were also resistant to proteasomal degradation. The dominant negative effect of K6-modified ubiquitin was further demonstrated in intact cells. Overexpression of K6W mutant ubiquitin resulted in accumulation of intracellular ubiquitin conjugates, stabilization of typical substrates for the ubiquitin-dependent proteolysis, and enhanced susceptibility to oxidative stress. Taken together, these results show that K6-modified ubiquitin is a potent and specific inhibitor of ubiquitin-mediated protein degradation.
J. Biol. Chem, 10.1074/jbc.M414356200
Submitted on December 21, 2004
Revised on March 24, 2005
Accepted on March 24, 2005
LYS-6-modified ubiquitin inhibits ubiquitin-dependent protein degradation
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