Proteasome substrate degradation requires association plus extended peptide

Takeuchi, Junko; Chen, Hui; Coffino, Philip

doi:10.1038/sj.emboj.7601476

Cited by 120 publications

(150 citation statements)

References 31 publications

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“…In addition to requiring a mechanism for binding to the proteasome, the efficient degradation of proteasomal substrates can involve poorly structured regions in their termini, from which unfolding or degradation is initiated (Prakash et al, 2004;Takeuchi et al, 2007). During ubiquitin-independent degradation of the enzyme ornithine decarboxylase, both these requirements are supplied by a stretch of 37 C-terminal residues (Takeuchi et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

et al. 2011

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Fos-related antigen-1 (Fra-1) is a member of the Activator Protein-1 (AP-1) transcription factor superfamily that is overexpressed in a variety of cancers, including colon, breast, lung, bladder and brain. High Fra-1 levels are associated with enhanced cell proliferation, survival, migration and invasion. Despite its frequent overexpression, the molecular mechanisms that regulate the accumulation of Fra-1 proteins in tumour cells are not well understood. Here, we show that turnover of Fra-1, which does not require ubiquitylation, is cooperatively regulated by two distinct mechanisms-association with the 19S proteasomal subunit, TBP-1, and by a C-terminal degron, which acts independently of TBP-1, but is regulated by RAS-ERK (extracellular signal-regulated kinase) signalling. TBP-1 depletion stabilized Fra-1 and further increased its levels in tumour cells expressing RAS-ERK pathway oncogenes. These effects correlated with increased AP-1 transcriptional activity. We suggest that during Fra-1 degradation, association with TBP-1 provides a mechanism for ubiquitin-independent proteasomal recognition, while the C terminus of the protein regulates its subsequent proteolytic processing.

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Section: Discussionmentioning

confidence: 99%

“…During ubiquitin-independent degradation of the enzyme ornithine decarboxylase, both these requirements are supplied by a stretch of 37 C-terminal residues (Takeuchi et al, 2007). Like ornithine decarboxylase, Fra-1 contains a 30-40 residue long C-terminal region (DEST domain) that is poorly structured .…”

Section: Discussionmentioning

confidence: 99%

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

et al. 2011

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“…Ubiquitination by itself does not always lead to rapid degradation [30,31] and effective proteolysis of a folded protein requires the presence of an unstructured region in the substrate [32,33], either at the ends of the polypeptide chain or internally [32,34]. The unstructured regions serves as the degradation initiation site and proteolysis continues from there along the polypeptide chain.…”

Section: A Second Step In Ubiquitin-dependent Proteasome Targetingmentioning

confidence: 99%

“…During activation, the IκB is degraded by the proteasome without affecting the other subunits of NFκB [46]. The explanation for these observations seemed to be that degradation begins specifically at the ubiquitination site but we now know that this mechanism may not always apply [32,33]. It will be interesting to determine whether the two components of the targeting signal could work together when separated onto two different polypeptides chains in a complex.…”

Section: A Second Step In Ubiquitin-dependent Proteasome Targetingmentioning

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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“…It was also observed that susceptibility to proteasomal degradation is affected by structural elements near the degradation sites (19). Additionally, the presence of an unstructured region can initiate the unfolding step and greatly facilitates the degradation process (28,29).…”

mentioning

confidence: 99%

Ubiquitin not only serves as a tag but also assists degradation by inducing protein unfolding

Hagai

Levy

2010

Proc. Natl. Acad. Sci. U.S.A.

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Protein ubiquitination controls the cellular fate of numerous eukaryotic proteins. Despite its importance, many fundamental questions remain regarding its mechanism. One such question is how ubiquitination alters the biophysical properties of the modified protein and whether these alterations are significant in the cellular context. In this study, we investigate the effects of ubiquitination on the folding thermodynamics and mechanism of various substrates using computational tools and find that ubiquitination changes the thermal stability of modified proteins in a manner relevant to cellular processes. These changes depend on the substrate modification site and on the type of ubiquitination. Ubiquitination of the substrate Ubc7 at the residues that are modified in vivo prior to proteasomal degradation uniquely results in significant thermal destabilization and a local unwinding near the modification site, which indicates that ubiquitination possibly facilitates the unfolding process and improves substrate degradation efficiency. With respect to the substrate p19 4inkd , our results support a synergetic effect of ubiquitination and phosphorylation on the degradation process via enhanced thermal destabilization. Our study implies that, in addition to its known role as a recognition signal, the ubiquitin attachment may be directly involved in the cellular process it regulates by changing the biophysical properties of the substrate.coarse-grained simulations | posttranslational modifications | protein degradation | protein folding | ubiquitination

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Proteasome substrate degradation requires association plus extended peptide

Cited by 120 publications

References 31 publications

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

Protein targeting to ATP-dependent proteases

Ubiquitin not only serves as a tag but also assists degradation by inducing protein unfolding

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