The base of the proteasome regulatory particle exhibits chaperone-like activity

Braun, Beate C.; Glickman, Michael S.; Kraft, Regine; Dahlmann, Burkhardt; Kloetzel, Peter M.; Finley, Daniel; Schmidt, Marion

doi:10.1038/12043

Cited by 446 publications

(256 citation statements)

References 29 publications

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“…The lid harbors nine other Rpn subunits (Rpn3, Rpn5-9, Rpn11-12 and Rpn15) (Tomko and Hochstrasser, 2011;Wolf and Hilt, 2004). The AAA+ proteins (Rpt1-6) of 19S regulatory complexes selectively bind and unfold substrate proteins, open the gate of 20S core particle and facilitate the vectorial translocation of unfolded substrates into the catalytic chamber for proteolysis (Braun et al, 1999;Smith et al, 2005).…”

Section: Figure 11: the Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Figure 11: the Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…The Rpt2 subunit appears to be the only one required for CP opening and substrate entry (Kohler et al, 2001). Two independent studies attributed another function to the base ATPases, in preventing protein aggregation, by acting as chaperones, and in mediating protein refolding and not unfolding (Braun et al, 1999), and the Rpt5 subunit may also bind polyubiquitin chains as shown by crosslinking studies (Lam et al, 2002).…”

Section: Proteasomementioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

114

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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“…These degradation signals also serve as both the protease binding site and the degradation initiation site. Finally, the proteasome can interact with misfolded or natively unfolded proteins lacking any known targeting signals in an ubiquitin-independent manner [61,62]. However, the relevance of this interaction to protein degradation is not clear.…”

Section: Targeting Signals In the Primary Sequence Of The Substratesmentioning

confidence: 99%

Protein targeting to ATP-dependent proteases

Inobe

Matouschek

2008

Current Opinion in Structural Biology

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ATP-dependent proteases control diverse cellular processes by degrading specific regulatory proteins. Understanding how these regulatory proteins are targeted to ATP-dependent proteases is of central importance to understanding their biological role as regulators. Recent work has shown that protein substrates are specifically transferred to ATP-dependent proteases through different routes. These routes can function in parallel or independently. In all of these targeting mechanisms it can be useful to separate two steps: substrate binding to the protease and initiation of degradation.To be active, newly synthesized protein chains must fold into three-dimensional structures, but regulated unfolding is also critically important in some biological processes, such as protein degradation by ATP-dependent proteases and protein translocation across membranes [1]. Unfolding is required during degradation because the proteolytic sites of the ATP-dependent proteases are sequestered deep inside the proteases' structures and accessible only through narrow openings. Similarly, unfolding is required during several translocation processes because the protein import channels in some organelles are not wide enough for native proteins to fit through them. The mechanisms of unfolding in both types of processes are similar to each other but different from that of unfolding induced by heat or chemical denaturants. Here we discuss how the requirement for protein unfolding during degradation affects the way ATPdependent proteases select their substrates. ATP-dependent proteasesATP-dependent proteases degrade short-lived regulatory proteins and thereby control cellular processes such as signal transduction, cell cycle, and gene transcription. The proteases also clear misfolded and aggregated proteins from the cell and produce some of the peptides to be displayed at cell surface as part of adaptive immune response. In eukaryotes, these functions are performed mainly by the proteasome. In prokaryotes and the organelles of eukaryotes, the functions are fulfill by analogues of the proteasome, such as the ClpAP, ClpXP, HslUV, FtsH, and Lon proteases. Although ATP-dependent proteases show only relatively little sequence identity, they share a common architecture [2].The ATP-dependent proteases all form large multisubunit particles (Figure 1). In the simplest case, FtsH protease, the particle consists 6 copies of a 71 kDa subunit forming a complex of approximately 425 kDa, and in the most complex case, the proteasome, the particle consists of some 40 different subunits forming a complex of 2 MDa molecular weight [3,4]. The subunits are mostly arranged in six or seven subunit rings that stack on top of each other to

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The base of the proteasome regulatory particle exhibits chaperone-like activity

Cited by 446 publications

References 29 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Protein targeting to ATP-dependent proteases

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