Proteins containing the UBA domain are able to bind to multi-ubiquitin chains

Wilkinson, Caroline R.M.; Seeger, Michael; Hartmann‐Petersen, Rasmus; Stone, Miranda; Wallace, Mark N.; Semple, Colin A.; Gordon, Colin

doi:10.1038/ncb1001-939

Cited by 381 publications

(379 citation statements)

References 19 publications

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“…Several lines of evidence support this receptor hypothesis. In rad23 and dsk2 mutant cells, substrates are ubiquitinated but not degraded, consistent with a role in substrate delivery (Lambertson et al, 1999;Wilkinson et al, 2001;Chen and Madura, 2002;Funakoshi et al, 2002;Rao and Sastry, 2002;Saeki et al, 2002a). Moreover, both the UbL and UBA domains of Rad23 are essential for its role in promoting proteolysis (Bertolaet et al, 2001b;Lambertson et al, 2003;Rao and Sastry, 2002).…”

Section: Introductionmentioning

confidence: 90%

“…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 second class of polyubiquitinbinding proteins, referred to as ubiquitin-like/ubiquitin-associated (UbL/UBA) proteins, is exemplified in yeast by the nucleotide excision repair protein Rad23 (Watkins et al, 1993) and the spindle pole duplication factor Dsk2 (Biggins et al, 1996). UbL/UBA proteins specifically recognize polyubiquitin chains via C-terminal UBA domains (Bertolaet et al, 2001b;Wilkinson et al, 2001;Hofmann and Bucher, 1996;Rao and Sastry, 2002;Chen and Madura, 2002;Raasi and Pickart, 2003). For example, Rad23 has two UBA domains that interact with polyubiquitinated proteins in a linkagespecific and chain length-dependent manner, preferentially binding to the K48-linked ubiquitin chains that serve as a degradation signal (Raasi and Pickart, 2003).…”

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confidence: 99%

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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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Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…or linear [104][105][106][107][108]. A large study by Raasi and coworkers pinpointed the specificity of 30 of these domains [109].…”

Section: Tandem Ubiquitin Binding Entity (Tube) Based Enrichmentmentioning

confidence: 99%

Proteomic techniques to probe the ubiquitin landscape

2015

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“…Budding yeast Dsk2 is a UBL-UBA protein that helps deliver polyubiquitinated proteins to the proteasome [17][18][19]. To better understand the molecular mechanisms of UBL-UBA proteins in the ubiquitin-proteasome pathway, we investigated the role of Dsk2 ubiquitination using lysine mutants of the Dsk2 UBL domain.…”

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confidence: 99%

Ubiquitin chains in the Dsk2 UBL domain mediate Dsk2 stability and protein degradation in yeast

Sekiguchi

Sasaki

Funakoshi

et al. 2011

Biochemical and Biophysical Research Communications

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Ubiquitin-like (UBL) -ubiquitin-associated (UBA) proteins, including Dsk2 and Rad23, act as delivery factors that target polyubiquitinated substrates to the proteasome. We report here that the Dsk2 UBL domain is ubiquitinated in yeast cells and that Dsk2 ubiquitination of the UBL domain is involved in Dsk2 stability, depending on the Dsk2 UBA domain. Also, Dsk2 lacking ubiquitin chains impaired ubiquitin-dependent protein degradation and decreased the interaction of Dsk2 with polyubiquitinated proteins in cells. Moreover, Dsk2 ubiquitination affected ability to restore the temperature-sensitive growth defect of dsk2 . These results indicate that ubiquitination in the UBL domain of Dsk2 has in vivo functions in the ubiquitin-proteasome pathway in yeast.

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Proteins containing the UBA domain are able to bind to multi-ubiquitin chains

Cited by 381 publications

References 19 publications

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

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

Proteomic techniques to probe the ubiquitin landscape

Ubiquitin chains in the Dsk2 UBL domain mediate Dsk2 stability and protein degradation in yeast

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