Potential allosteric modulators of the proteasome activity |
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Authors: | E Jankowska E Sikorska R Rostankowski S Madabhushi M Tokmina‐Lukaszewska F Kasprzykowski |
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Institution: | 1. Faculty of Chemistry, University of Gdansk, Sobieskiego 18, Gdansk 80‐952, PolandE. Jankowska, M. Gaczynska, P. Osmulski contributed equally to this work;2. Faculty of Chemistry, University of Gdansk, Sobieskiego 18, Gdansk 80‐952, Poland;3. Institute of Biotechnology, University of Texas Health Science Center, 15355 Lambda Dr, San Antonio, Texas 78245 |
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Abstract: | Proteasome, consisting of a tube‐shaped proteolytic core particle and attached to it regulatory modules, is a multifunctional enzymatic complex essential for the ubiquitin‐proteasome metabolic pathway. Due to its immense involvement in regulation of cellular physiology, the proteasome is an acknowledged anticancer drug target and potential target to treat inflammatory or degenerative diseases. So far, competitive inhibitors of the core particle gain most consideration as drugs. We postulate that noncompetitively‐acting small‐molecule compounds would provide excellent means to precisely regulate actions of the proteasome. In this study, we evaluated five short peptides based on sequences of two proteins known to interact with the core proteasome: HIV‐1 Tat and PA28/REG activator. We performed Circular Dichroism (CD), Fourier Transformed Infrared Spectroscopy (FTIR), and Nuclear Magnetic Resonance (NMR) analysis, supplemented by MD simulations, and tested influence of the peptides on performance of the core particle active sites and functioning of regulatory modules. We found that PP2‐containing Tat peptides are noncompetitive inhibitors of the core, interfering with the actions of PA28αβ activator. In addition, at low concentrations the turn‐prone Tat2 is able to activate the latent core. The random coil‐structured PA28‐derived peptides display only weak or nondetectable direct effects on the core activities, exhibiting, however, a positive cooperation with activity‐enhancing actions of PA28αβ. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 481–495, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com |
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Keywords: | proteasome HIV‐1 Tat protein 11S activator allosteric inhibitor |
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