Periodate-Triggered Cross-Linking Reveals Sug2/Rpt4 as the Molecular Target of a Peptoid Inhibitor of the 19S Proteasome Regulatory Particle

Division of Translational Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9185, USA.
Journal of the American Chemical Society (Impact Factor: 12.11). 11/2007; 129(43):12936-7. DOI: 10.1021/ja075469+
Source: PubMed


This study describes the identification of the protein target of the first chemical inhibitor (RIP-1) of t he 19S regulatory particle (RP) of the 25S proteasome. Periodate-triggered chemical cross-linking of DOPA-conjugate RIP-1 and the 26S proteasome identified Sug2/Rpt4, one of the six ATPases in the 19S as the molecular target of RIP-1 for Sug2/Rpt4 was domonstarated by examining cross-linking reactions with each ATPase if tge 19S RP. RIP-1 should provide a useful biological tool to probe the various biological roles of Sug2/Rpt4.

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    • "However, in the 7 years since their discovery, no single study using these compounds has been published. One purine-capped peptoid inhibitor of the Rpt4 ATPase of the 19S RP has been reported (Lim et al., 2007). However, this compound has not been tested for off-target effects. "
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    ABSTRACT: Proteasomes are large, multisubunit proteolytic complexes presenting multiple targets for therapeutic intervention. The 26S proteasome consists of a 20S proteolytic core and one or two 19S regulatory particles. The 20S core contains three types of active sites. Many structurally diverse inhibitors of these active sites, both natural product and synthetic, have been discovered in the last two decades. One, bortezomib, is used clinically for treatment of multiple myeloma, mantle cell lymphoma, and acute allograft rejection. Five more recently developed proteasome inhibitors are in trials for treatment of myeloma and other cancers. Proteasome inhibitors also have activity in animal models of autoimmune and inflammatory diseases, reperfusion injury, promote bone and hair growth, and can potentially be used as anti-infectives. In addition, inhibitors of ATPases and deubiquitinases of 19S regulatory particles have been discovered in the last decade.
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    ABSTRACT: The 26S proteasome is a multi-subunit complex that has a barrel-shaped peptidase core (CP) whose proteolytic activity is sequestered from the cellular milieu by two regulatory particles (RP) that are docked on either end. The RP confers ubiquitin and ATP dependence to the proteolytic process. The CP can also be regulated by the REGγ complex, and can, in some instances, catalyze the degradation of proteins independent of ATP and ubiquitin. The peptidase activity of the 20S CP has been validated as a therapeutic target for cancers such as multiple myeloma by the development of inhibitors such as VELCAID. Since the peptidase activity is so central to 26S proteasome function, inhibitors of this class are generally toxic. Alternative therapeutic targets within the 26S proteasome can be explored, given the multistep nature of regulated degradation. Specifically, the recognition, and deubiquitination, of the polyubiquitin chain, and the unfolding and gating steps can be targeted. Keywords26S proteasome–26S proteasome inhibitors–Ubiquitin chain receptors–Unfoldases–Gating–Deubiquitination
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