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Science 298 (5593): 611-615

Copyright © 2002 by the American Association for the Advancement of Science

Role of Rpn11 Metalloprotease in Deubiquitination and Degradation by the 26S Proteasome

Rati Verma,1 L. Aravind,2 Robert Oania,1 W. Hayes McDonald,3 John R. Yates III,3 Eugene V. Koonin,2 Raymond J. Deshaies1*

The 26S proteasome mediates degradation of ubiquitin-conjugated proteins. Although ubiquitin is recycled from proteasome substrates, the molecular basis of deubiquitination at the proteasome and its relation to substrate degradation remain unknown. The Rpn11 subunit of the proteasome lid subcomplex contains a highly conserved Jab1/MPN domain-associated metalloisopeptidase (JAMM) motif--EXnHXHX10D. Mutation of the predicted active-site histidines to alanine (rpn11AXA) was lethal and stabilized ubiquitin pathway substrates in yeast. Rpn11AXA mutant proteasomes assembled normally but failed to either deubiquitinate or degrade ubiquitinated Sic1 in vitro. Our findings reveal an unexpected coupling between substrate deubiquitination and degradation and suggest a unifying rationale for the presence of the lid in eukaryotic proteasomes.

1 Department of Biology and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125, USA.
2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
3 Department of Cell Biology, The Scripps Research Institute, San Diego, CA 92037, USA.
*   To whom correspondence should be addressed. E-mail: deshaies{at}caltech.edu



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A. Amerik, N. Sindhi, and M. Hochstrasser (2006)
J. Cell Biol. 175, 825-835
   Abstract »    Full Text »    PDF »
A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes.
J. Hamazaki, S.-i. Iemura, T. Natsume, H. Yashiroda, K. Tanaka, and S. Murata (2006)
EMBO J. 25, 4524-4536
   Abstract »    Full Text »    PDF »
Jab1 Induces the Cytoplasmic Localization and Degradation of p53 in Coordination with Hdm2.
W. Oh, E.-W. Lee, Y. H. Sung, M.-R. Yang, J. Ghim, H.-W. Lee, and J. Song (2006)
J. Biol. Chem. 281, 17457-17465
   Abstract »    Full Text »    PDF »
The 19 S Proteasomal Subunit POH1 Contributes to the Regulation of c-Jun Ubiquitination, Stability, and Subcellular Localization.
J. F. Nabhan and P. Ribeiro (2006)
J. Biol. Chem. 281, 16099-16107
   Abstract »    Full Text »    PDF »
The Proteasome Pathway Destabilizes Yersinia Outer Protein E and Represses Its Antihost Cell Activities.
K. Ruckdeschel, G. Pfaffinger, K. Trulzsch, G. Zenner, K. Richter, J. Heesemann, and M. Aepfelbacher (2006)
J. Immunol. 176, 6093-6102
   Abstract »    Full Text »    PDF »
Ubiquitin binding by a variant Jab1/MPN domain in the essential pre-mRNA splicing factor Prp8p.
P. BELLARE, A. K. KUTACH, A. K. RINES, C. GUTHRIE, and E. J. SONTHEIMER (2006)
RNA 12, 292-302
   Abstract »    Full Text »    PDF »
Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14.
M. Hu, P. Li, L. Song, P. D. Jeffrey, T. A. Chernova, K. D. Wilkinson, R. E. Cohen, and Y. Shi (2005)
EMBO J. 24, 3747-3756
   Abstract »    Full Text »    PDF »
Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes.
E. Mizuno, T. Iura, A. Mukai, T. Yoshimori, N. Kitamura, and M. Komada (2005)
Mol. Biol. Cell 16, 5163-5174
   Abstract »    Full Text »    PDF »
The RPN1 Subunit of the 26S Proteasome in Arabidopsis Is Essential for Embryogenesis.
V. Brukhin, J. Gheyselinck, V. Gagliardini, P. Genschik, and U. Grossniklaus (2005)
PLANT CELL 17, 2723-2737
   Abstract »    Full Text »    PDF »
Structural Basis for Interaction between the Ubp3 Deubiquitinating Enzyme and Its Bre5 Cofactor.
K. Li, K. Zhao, B. Ossareh-Nazari, G. Da, C. Dargemont, and R. Marmorstein (2005)
J. Biol. Chem. 280, 29176-29185
   Abstract »    Full Text »    PDF »

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