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Science 298 (5593): 608-611

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

Role of Predicted Metalloprotease Motif of Jab1/Csn5 in Cleavage of Nedd8 from Cul1

Gregory A. Cope,1 Greg S. B. Suh,3* L. Aravind,4 Sylvia E. Schwarz,1dagger S. Lawrence Zipursky,23 Eugene V. Koonin,4 Raymond J. Deshaies12ddagger

COP9 signalosome (CSN) cleaves the ubiquitin-like protein Nedd8 from the Cul1 subunit of SCF ubiquitin ligases. The Jab1/MPN domain metalloenzyme (JAMM) motif in the Jab1/Csn5 subunit was found to underlie CSN's Nedd8 isopeptidase activity. JAMM is found in proteins from archaea, bacteria, and eukaryotes, including the Rpn11 subunit of the 26S proteasome. Metal chelators and point mutations within JAMM abolished CSN-dependent cleavage of Nedd8 from Cul1, yet had little effect on CSN complex assembly. Optimal SCF activity in yeast and both viability and proper photoreceptor cell (R cell) development in Drosophila melanogaster required an intact Csn5 JAMM domain. We propose that JAMM isopeptidases play important roles in a variety of physiological pathways.

1 Department of Biology, California Institute of Technology (CalTech), Pasadena, CA 91125, USA.
2 Howard Hughes Medical Institute,
3 Department of Biological Chemistry, The School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA 90095, USA.
4 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
*   Present address: Department of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

dagger    Present address: G2M Cancer Drugs AG, Frankfurt/Main, Germany.

ddagger    To whom correspondence should be addressed. E-mail: deshaies{at}

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X. S. Puente and C. Lopez-Otin (2004)
Genome Res. 14, 609-622
   Abstract »    Full Text »    PDF »
Complementary Roles for Rpn11 and Ubp6 in Deubiquitination and Proteolysis by the Proteasome.
A. Guterman and M. H. Glickman (2004)
J. Biol. Chem. 279, 1729-1738
   Abstract »    Full Text »    PDF »
Specific and Covalent Targeting of Conjugating and Deconjugating Enzymes of Ubiquitin-Like Proteins.
J. Hemelaar, A. Borodovsky, B. M. Kessler, D. Reverter, J. Cook, N. Kolli, T. Gan-Erdene, K. D. Wilkinson, G. Gill, C. D. Lima, et al. (2004)
Mol. Cell. Biol. 24, 84-95
   Abstract »    Full Text »    PDF »
Encore facilitates SCF-Ubiquitin-proteasome-dependent proteolysis during Drosophila oogenesis.
J. T. Ohlmeyer and T. Schupbach (2003)
Development 130, 6339-6349
   Abstract »    Full Text »    PDF »
Disruption of the COP9 Signalosome Csn2 Subunit in Mice Causes Deficient Cell Proliferation, Accumulation of p53 and Cyclin E, and Early Embryonic Death.
K. Lykke-Andersen, L. Schaefer, S. Menon, X.-W. Deng, J. B. Miller, and N. Wei (2003)
Mol. Cell. Biol. 23, 6790-6797
   Abstract »    Full Text »    PDF »
COP9 Signalosome Subunit 3 Is Essential for Maintenance of Cell Proliferation in the Mouse Embryonic Epiblast.
J. Yan, K. Walz, H. Nakamura, S. Carattini-Rivera, Q. Zhao, H. Vogel, N. Wei, M. J. Justice, A. Bradley, and J. R. Lupski (2003)
Mol. Cell. Biol. 23, 6798-6808
   Abstract »    Full Text »    PDF »
Use of RNA Interference and Complementation To Study the Function of the Drosophila and Human 26S Proteasome Subunit S13.
J. Lundgren, P. Masson, C. A. Realini, and P. Young (2003)
Mol. Cell. Biol. 23, 5320-5330
   Abstract »    Full Text »    PDF »
DEN1 Is a Dual Function Protease Capable of Processing the C Terminus of Nedd8 and Deconjugating Hyper-neddylated CUL1.
K. Wu, K. Yamoah, G. Dolios, T. Gan-Erdene, P. Tan, A. Chen, C.-g. Lee, N. Wei, K. D. Wilkinson, R. Wang, et al. (2003)
J. Biol. Chem. 278, 28882-28891
   Abstract »    Full Text »    PDF »
Identification and Characterization of DEN1, a Deneddylase of the ULP Family.
T. Gan-Erdene, K. Nagamalleswari, L. Yin, K. Wu, Z.-Q. Pan, and K. D. Wilkinson (2003)
J. Biol. Chem. 278, 28892-28900
   Abstract »    Full Text »    PDF »
NEDP1, a Highly Conserved Cysteine Protease That deNEDDylates Cullins.
H. M. Mendoza, L.-n. Shen, C. Botting, A. Lewis, J. Chen, B. Ink, and R. T. Hay (2003)
J. Biol. Chem. 278, 25637-25643
   Abstract »    Full Text »    PDF »
A Novel Type of Deubiquitinating Enzyme.
P. C. Evans, T. S. Smith, M.-J. Lai, M. G. Williams, D. F. Burke, K. Heyninck**, M. M. Kreike, R. Beyaert, T. L. Blundell, and P. J. Kilshaw (2003)
J. Biol. Chem. 278, 23180-23186
   Abstract »    Full Text »    PDF »

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