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Science 299 (5605): 408-411

Copyright © 2003 by the American Association for the Advancement of Science

Endoproteolytic Activity of the Proteasome

Chang-Wei Liu, Michael J. Corboy, George N. DeMartino,* Philip J. Thomas*

The proteasome plays a central role in the degradation of regulatory and misfolded proteins. Current models suggest that substrates access the internal catalytic sites by processively threading their termini through the gated substrate channel. Here, we found that latent (closed) and activated (open) proteasomes degraded two natively disordered substrates at internal peptide bonds even when they lacked accessible termini, suggesting that these substrates themselves promoted gating of the proteasome. This endoproteolysis provides a molecular mechanism for regulated release of transcription factors from inactive precursors as well as a means of accessing internal folding defects of misfolded multidomain proteins.

Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
*   To whom correspondence should be addressed. E-mail: philip.thomas{at} (P.J.T.); george.demartino{at} (G.N.D.)

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Proteasome substrate degradation requires association plus extended peptide.
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Widespread, but Non-identical, Association of Proteasomal 19 and 20 S Proteins with Yeast Chromatin.
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J. Biol. Chem. 281, 27346-27355
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An antigen produced by splicing of noncontiguous peptides in the reverse order..
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Archaeal Proteasomes Effectively Degrade Aggregation-prone Proteins and Reduce Cellular Toxicities in Mammalian Cells.
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Multisite Protein Kinase A and Glycogen Synthase Kinase 3{beta} Phosphorylation Leads to Gli3 Ubiquitination by SCF{beta}TrCP.
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The 20S proteasome processes NF-{kappa}B1 p105 into p50 in a translation-independent manner.
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Histone Deacetylase Inhibitors Induce VHL and Ubiquitin-Independent Proteasomal Degradation of Hypoxia-Inducible Factor 1{alpha}.
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Mol. Cell. Biol. 26, 2019-2028
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Hzf, a p53-Responsive Gene, Regulates Maintenance of the G2 Phase Checkpoint Induced by DNA Damage.
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Chemical Blockage of the Proteasome Inhibitory Function of Bortezomib: IMPACT ON TUMOR CELL DEATH.
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J. Biol. Chem. 280, 22670-22678
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PNAS 102, 2162-2167
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{alpha}-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines.
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J. Biol. Chem. 279, 52984-52990
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Functional Consequences of {alpha}-Synuclein Tyrosine Nitration: DIMINISHED BINDING TO LIPID VESICLES AND INCREASED FIBRIL FORMATION.
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J. Biol. Chem. 279, 47746-47753
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Distinct Machinery Is Required in Saccharomyces cerevisiae for the Endoplasmic Reticulum-associated Degradation of a Multispanning Membrane Protein and a Soluble Luminal Protein.
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J. Biol. Chem. 279, 38369-38378
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N-Terminal Ubiquitination of Extracellular Signal-Regulated Kinase 3 and p21 Directs Their Degradation by the Proteasome.
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   Abstract »    Full Text »    PDF »
Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy.
C. Wojcik and M. Di Napoli (2004)
Stroke 35, 1506-1518
   Abstract »    Full Text »    PDF »
Repeat Sequence of Epstein-Barr Virus-encoded Nuclear Antigen 1 Protein Interrupts Proteasome Substrate Processing.
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J. Biol. Chem. 279, 8635-8641
   Abstract »    Full Text »    PDF »
Clearance of {alpha}-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway.
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J. Neurosci. 24, 1888-1896
   Abstract »    Full Text »    PDF »
Complementary Roles for Rpn11 and Ubp6 in Deubiquitination and Proteolysis by the Proteasome.
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J. Biol. Chem. 279, 1729-1738
   Abstract »    Full Text »    PDF »
Quantitative Analysis of Prion-Protein Degradation by Constitutive and Immuno-20S Proteasomes Indicates Differences Correlated with Disease Susceptibility.
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J. Immunol. 172, 1083-1091
   Abstract »    Full Text »    PDF »
Ubiquitination of {alpha}-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function.
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J. Biol. Chem. 278, 44405-44411
   Abstract »    Full Text »    PDF »
Use of Modular Substrates Demonstrates Mechanistic Diversity and Reveals Differences in Chaperone Requirement of ERAD.
C. Taxis, R. Hitt, S.-H. Park, P. M. Deak, Z. Kostova, and D. H. Wolf (2003)
J. Biol. Chem. 278, 35903-35913
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Stability of the Rel Homology Domain Is Critical for Generation of NF-{kappa}B p50 Subunit.
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J. Biol. Chem. 278, 31479-31485
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An Ubiquitin Ligase Recognizing a Protein Oxidized by Iron: Implications for the Turnover of Oxidatively Damaged Proteins.
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J. Biochem. 134, 175-182
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Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains.
Y. Ye, H. H. Meyer, and T. A. Rapoport (2003)
J. Cell Biol. 162, 71-84
   Abstract »    Full Text »    PDF »

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