Rad23 and Rpn10 Serve as Alternative Ubiquitin Receptors for the Proteasome

Elsasser, Suzanne; Chandler-Militello, Devin; Müller, Boje; Hanna, John; Finley, Daniel

doi:10.1074/jbc.m404020200

Cited by 307 publications

(297 citation statements)

References 49 publications

(61 reference statements)

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“…RP1CP and RP2CP refer to singly or doubly 19 S capped 20 S proteasomes, respectively. Active proteasome was purified and analyzed by nondenaturating PAGE as described (61). C, a siRNA-mediated knockdown of hRpn10 does not affect parkin binding to proteasome.…”

Section: Resultsmentioning

confidence: 99%

The E3 Ubiquitin Ligase Parkin Is Recruited to the 26 S Proteasome via the Proteasomal Ubiquitin Receptor Rpn13

Aguileta

Korać

Durcan

et al. 2015

Journal of Biological Chemistry

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Background:The role of the N-terminal ubiquitin-like domain of the E3 ligase parkin is not fully understood. Results: Parkin is recruited to the 26 S proteasome through the interaction of its ubiquitin-like domain with the intrinsic proteasomal ubiquitin receptor Rpn13. Conclusion: Parkin turnover and E3 ligase activity can be regulated by its recruitment to the 26 S proteasome via Rpn13. Significance: Parkin-Rpn13 interaction might be exploited as a potential therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

The E3 Ubiquitin Ligase Parkin Is Recruited to the 26 S Proteasome via the Proteasomal Ubiquitin Receptor Rpn13

Aguileta

Korać

Durcan

et al. 2015

Journal of Biological Chemistry

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“…In eukaryotes, the DNA repair proteins Rad23 and Dsk2 can target ubiquitinated proteins for degradation [63,64]. They interact with the proteasome through a ubiquitin-like domain (UBL) and with the ubiquitin modification in substrates through two ubiquitinassociation domains (UBAs) [37,38,63,[65][66][67]. Thus, UBL-UBA proteins appear to deliver ubiquitinated proteins to the proteasome where they are subsequently degraded.…”

Section: Adapter Proteinsmentioning

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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“…On the contrary, recent work has shown that a diverse set of ubiquitin-binding receptors regulate the targeting of ubiquitinated proteins to the proteasome in a substratespecific manner (Wilkinson et al, 2001;Chen and Madura, 2002;Elsasser et al, 2004;Verma et al, 2004; for review, see Elsasser and Finley, 2005;Hicke et al, 2005). The first polyubiquitin-binding receptor identified was Rpn10, a subunit of the 19S regulatory complex that contains a ubiquitin-interacting motif (Deveraux et al, 1994 tional ubiquitin chain recognition mechanisms must exist (van Nocker et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

A Conditional Yeast E1 Mutant Blocks the Ubiquitin–Proteasome Pathway and Reveals a Role for Ubiquitin Conjugates in Targeting Rad23 to the Proteasome

Ghaboosi

Deshaies

2007

MBoC

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E1 ubiquitin activating enzyme catalyzes the initial step in all ubiquitin-dependent processes. We report the isolation of uba1-204, a temperature-sensitive allele of the essential Saccharomyces cerevisiae E1 gene, UBA1. Uba1-204 cells exhibit dramatic inhibition of the ubiquitin-proteasome system, resulting in rapid depletion of cellular ubiquitin conjugates and stabilization of multiple substrates. We have employed the tight phenotype of this mutant to investigate the role ubiquitin conjugates play in the dynamic interaction of the UbL/UBA adaptor proteins Rad23 and Dsk2 with the proteasome. Although proteasomes purified from mutant cells are intact and proteolytically active, they are depleted of ubiquitin conjugates, Rad23, and Dsk2. Binding of Rad23 to these proteasomes in vitro is enhanced by addition of either free or substrate-linked ubiquitin chains. Moreover, association of Rad23 with proteasomes in mutant and wild-type cells is improved upon stabilizing ubiquitin conjugates with proteasome inhibitor. We propose that recognition of polyubiquitin chains by Rad23 promotes its shuttling to the proteasome in vivo. INTRODUCTIONActivation of ubiquitin by ubiquitin-activating enzyme (E1) is the requisite first step in all ubiquitin-dependent pathways, including regulated proteolysis. The process begins with an ATP-dependent reaction in which the ubiquitin moiety forms a high-energy thioester bond with the active site cysteine of E1. E1 can then transfer the activated ubiquitin to a conjugating enzyme (E2), which acts alone or in conjunction with a ubiquitin ligase (E3) to covalently link ubiquitin to lysine residues on specific target proteins (Haas and Siepmann, 1997). Through successive ligation reactions, a polyubiquitin chain can form on the substrate and serve as a signal for targeting to the multisubunit 26S proteasome. Composed of a cylindrical 20S proteolytic core complex capped at one or both ends by 19S regulatory complexes, the proteasome deubiquitinates and unfolds substrates before translocating them into its core for proteolysis (Amerik and Hochstrasser, 2004;Pickart and Cohen, 2004).The existence of mammalian cell lines that carry temperature-sensitive alleles of E1 has been of great importance to the study of the functions of the ubiquitin system in animal cells Finley et al., 1984;Kulka et al., 1988;Salvat et al., 2000). Ironically, no tight, rapid-acting conditional mutation has been described for the budding yeast UBA1 gene that encodes E1 despite the availability of sophisticated molecular genetic techniques in this organism.Although a temperature-sensitive allele of UBA1 exists, this allele results in only moderate stabilization of tested substrates and possible defects in ubiquitination were not examined (McGrath, 1991;Gandre and Kahana, 2002). A second allele resulting from a transposon insertion upstream of the UBA1 coding sequence reduced wild-type Uba1 protein function, causing inefficient degradation of some proteins (Swanson and Hochstrasser, 2000). Additional alleles were later en...

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Rad23 and Rpn10 Serve as Alternative Ubiquitin Receptors for the Proteasome

Cited by 307 publications

References 49 publications

The E3 Ubiquitin Ligase Parkin Is Recruited to the 26 S Proteasome via the Proteasomal Ubiquitin Receptor Rpn13

The E3 Ubiquitin Ligase Parkin Is Recruited to the 26 S Proteasome via the Proteasomal Ubiquitin Receptor Rpn13

Protein targeting to ATP-dependent proteases

A Conditional Yeast E1 Mutant Blocks the Ubiquitin–Proteasome Pathway and Reveals a Role for Ubiquitin Conjugates in Targeting Rad23 to the Proteasome

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