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Formation of Proteasome−PA700 Complexes Directly Correlates with Activation of Peptidase Activity

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School of Biological Sciences, University of Missouri−Kansas City, Kansas City, Missouri 64110, and Howard Hughes Medical Institute and Departments of Biochemistry and Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75235
Cite this: Biochemistry 1998, 37, 37, 12927–12932
Publication Date (Web):August 28, 1998
Copyright © 1998 American Chemical Society

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    The proteolytic activity of the eukaryotic 20S proteasome is stimulated by a multisubunit activator, PA700, which forms both 1:1 and 2:1 complexes with the proteasome. Formation of the complexes is enhanced by an additional protein assembly called modulator, which also stimulates the enzymatic activity of the proteasome only in the presence of PA700. Here we show that the binding of PA700 to the proteasome is cooperative, as is the activation of the proteasome's intrinsic peptidase activity. Modulator increases the extent of complex formation and peptidase activation, while preserving the cooperative kinetics. Furthermore, the increase in activity is not linear with the number of PA700 assemblies bound to the proteasome, but rather with the number of proteasome−PA700 complexes, regardless of the PA700:proteasome stoichiometry. Hence the stimulation of peptidase activity is fully (or almost fully) effected by the binding of a single PA700 to the 20S proteasome. The stimulation of peptidase by modulator is explained entirely by the increased number of proteasome−PA700 complexes formed in its presence, rather than by any substantial direct stimulation of catalysis. These observations are consistent with a model in which PA700, either alone or assisted by modulator, promotes conformational changes in the proteasome that activate the catalytic sites and/or facilitate access of peptide substrates to these sites.

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     This work was supported by grants from the University of Missouri Research Board and the National Insitutes of Health (GM57403 to E.P.G. and DK46181 to G.N.D.).

     School of Biological Sciences, University of Missouri−Kansas City.


     Howard Hughes Medical Institute and Department of Biochemistry, the University of Texas Southwestern Medical Center.

     Department of Physiology, the University of Texas Southwestern Medical Center.


     Corresponding author: School of Biological Sciences, UM−KC, 5100 Rockhill Rd., Kansas City, MO 64110. (816) 235-2584 (phone); (816) 235-1503 (fax); [email protected] (email).

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    5. Tiffany A. Thibaudeau, David M. Smith, . A Practical Review of Proteasome Pharmacology. Pharmacological Reviews 2019, 71 (2) , 170-197.
    6. Tiffany A. Thibaudeau, Raymond T. Anderson, David M. Smith. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nature Communications 2018, 9 (1)
    7. Xiaohua Li, David Thompson, Brajesh Kumar, George N. DeMartino. Molecular and Cellular Roles of PI31 (PSMF1) Protein in Regulation of Proteasome Function. Journal of Biological Chemistry 2014, 289 (25) , 17392-17405.
    8. Annika Höhn, Jeannette König, Tilman Grune. Protein oxidation in aging and the removal of oxidized proteins. Journal of Proteomics 2013, 92 , 132-159.
    9. . Removal of Oxidized Proteins. 2012, 215-293.
    10. Jian Xu, Shuangxi Wang, Miao Zhang, Qilong Wang, Sima Asfa, Ming-Hui Zou, . Tyrosine Nitration of PA700 Links Proteasome Activation to Endothelial Dysfunction in Mouse Models with Cardiovascular Risk Factors. PLoS ONE 2012, 7 (1) , e29649.
    11. Tobias Jung, Tilman Grune. Structure of the Proteasome. 2012, 1-39.
    12. George N. DeMartino. Reconstitution of PA700, the 19S Regulatory Particle, from Purified Precursor Complexes. 2012, 443-452.
    13. Young-Chan Kim, George N. DeMartino. C Termini of Proteasomal ATPases Play Nonequivalent Roles in Cellular Assembly of Mammalian 26 S Proteasome. Journal of Biological Chemistry 2011, 286 (30) , 26652-26666.
    14. Brajesh Kumar, Young-Chan Kim, George N. DeMartino. The C Terminus of Rpt3, an ATPase Subunit of PA700 (19 S) Regulatory Complex, Is Essential for 26 S Proteasome Assembly but Not for Activation. Journal of Biological Chemistry 2010, 285 (50) , 39523-39535.
    15. David Thompson, Kevin Hakala, George N. DeMartino. Subcomplexes of PA700, the 19 S Regulator of the 26 S Proteasome, Reveal Relative Roles of AAA Subunits in 26 S Proteasome Assembly and Activation and ATPase Activity. Journal of Biological Chemistry 2009, 284 (37) , 24891-24903.
    16. Minoru Funakoshi, Robert J. Tomko, Hideki Kobayashi, Mark Hochstrasser. Multiple Assembly Chaperones Govern Biogenesis of the Proteasome Regulatory Particle Base. Cell 2009, 137 (5) , 887-899.
    17. Shigeo Murata, Hideki Yashiroda, Keiji Tanaka. Molecular mechanisms of proteasome assembly. Nature Reviews Molecular Cell Biology 2009, 10 (2) , 104-115.
    18. Franziska Kriegenburg, Michael Seeger, Yasushi Saeki, Keiji Tanaka, Anne-Marie B. Lauridsen, Rasmus Hartmann-Petersen, Klavs B. Hendil. Mammalian 26S Proteasomes Remain Intact during Protein Degradation. Cell 2008, 135 (2) , 355-365.
    19. Monika Bajorek, Michael H. Glickman. Regulation of Proteolysis at the Proteasome Portal. 2008, 111-127.
    20. Monika Bajorek, Michael H. Glickman. The Proteasome Portal and Regulation of Proteolysis. 2007, 111-127.
    21. Keiji Tanaka, Hideki Yashiroda, Shigeo Murata. Ubiquity and Diversity of the Proteasome System. 2007, 129-156.
    22. Sabine Olivier, Pierre Robe, Vincent Bours. Can NF-κB be a target for novel and efficient anti-cancer agents?. Biochemical Pharmacology 2006, 72 (9) , 1054-1068.
    23. Monika Bajorek, Michael H. Glickman. The Proteasome Portal and Regulation of Proteolysis. 2005, 111-127.
    24. Keiji Tanaka, Hideki Yashiroda, Shigeo Murata. Ubiquity and Diversity of the Proteasome System. 2005, 129-156.
    25. Shalon E. Babbitt, Alexi Kiss, Andrew E. Deffenbaugh, Yie-Hwa Chang, Eric Bailly, Hediye Erdjument-Bromage, Paul Tempst, Tione Buranda, Larry A. Sklar, Jennifer Baumler, Edward Gogol, Dorota Skowyra. RETRACTED: ATP Hydrolysis-Dependent Disassembly of the 26S Proteasome Is Part of the Catalytic Cycle. Cell 2005, 121 (4) , 553-565.
    26. Cezary Wojcik. Rpt2. AfCS-Nature Molecule Pages 2005,
    27. Yasuhisa Oida, Began Gopalan, Ryo Miyahara, Satoshi Inoue, Cynthia D. Branch, Abner M. Mhashilkar, E. Lin, B. Nebiyou Bekele, Jack A. Roth, Sunil Chada, Rajagopal Ramesh. Sulindac enhances adenoviral vector expressing mda-7/IL-24 –mediated apoptosis in human lung cancer. Molecular Cancer Therapeutics 2005, 4 (2) , 291-304.
    28. George N. DeMartino. Purification of PA700, the 19S Regulatory Complex of the 26S Proteasome. 2005, 295-306.
    29. Peter F. Bross, Robert Kane, Ann T. Farrell, Sophia Abraham, Kimberly Benson, Margaret E. Brower, Sean Bradley, Jogarao V. Gobburu, Anwar Goheer, Shwu-Luan Lee, John Leighton, Cheng Yi Liang, Richard T. Lostritto, William D. McGuinn, David E. Morse, Atiqur Rahman, Lilliam A. Rosario, S. Leigh Verbois, Grant Williams, Yong-Cheng Wang, Richard Pazdur. Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma. Clinical Cancer Research 2004, 10 (12) , 3954-3964.
    30. Edor Kabashi, Jeffrey N. Agar, David M. Taylor, Sandra Minotti, Heather D. Durham. Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosis. Journal of Neurochemistry 2004, 89 (6) , 1325-1335.
    31. Melanie Ohi, Ying Li, Yifan Cheng, Thomas Walz. Negative staining and image classification — powerful tools in modern electron microscopy. Biological Procedures Online 2004, 6 (1) , 23-34.
    32. Michael H. Glickman, Aaron Ciechanover. The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction. Physiological Reviews 2002, 82 (2) , 373-428.
    33. Olivier Coux. The 26S Proteasome. 2002, 85-107.
    34. M. H. Glickman, V. Maytal. Regulating the 26S Proteasome. 2002, 43-72.
    35. Friedrich Kopp, Burkhardt Dahlmann, Lothar Kuehn. Reconstitution of hybrid proteasomes from purified PA700–20 S complexes and PA28αβ activator: ultrastructure and peptidase activities. Journal of Molecular Biology 2001, 313 (3) , 465-471.
    36. Steven Jon Russell, Fernando Gonzalez, Leemor Joshua-Tor, Stephen Albert Johnston. Selective chemical inactivation of AAA proteins reveals distinct functions of proteasomal ATPases. Chemistry & Biology 2001, 8 (10) , 941-950.
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    38. Peter Zwickl, Erika Seemüller, Barbara Kapelari, Wolfgang Baumeister. The proteasome: A supramolecular assembly designed for controlled proteolysis. 2001, 187-222.
    39. Arthur L. Horwich, Eilika U. Weber-Ban, Daniel Finley. Chaperone rings in protein folding and degradation. Proceedings of the National Academy of Sciences 1999, 96 (20) , 11033-11040.
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