Polyubiquitin substrates allosterically activate their own degradation by the 26S proteasome

Bech‐Otschir, Dawadschargal; Helfrich, Annett; Enenkel, Cordula; Consiglieri, Gesa; Seeger, Michael; Holzhütter, Hermann−Georg; Dahlmann, Burkhardt; Kloetzel, Peter M.

doi:10.1038/nsmb.1547

Cited by 65 publications

(68 citation statements)

References 34 publications

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“…Peptide hydrolysis is a monitor of 20 S proteasome gating and is promoted upon PA700 binding (18,20). However, gating does not appear to be a simple twostate function but rather is variably modulated by factors including the status of Rpt-bound ATP and binding of polyubiquitin by the assembled 26 S proteasome (35,49,58). Previous work demonstrated a role for ATP binding by Rpt2 in gating of yeast 26 S proteasome, an effect we were unable to evaluate here because of the assembly defect caused by ATP binding mutant Rpt2 (21).…”

Section: Discussionmentioning

confidence: 99%

ATP Binding by Proteasomal ATPases Regulates Cellular Assembly and Substrate-induced Functions of the 26 S Proteasome

Kim

Thompson

et al. 2013

Journal of Biological Chemistry

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Background: ATPase subunits mediate 26 S proteasome assembly and function. Results: Defective ATP binding by some ATPase subunits inhibits proteasome assembly, and proteasomes harboring an ATP binding-defective subunit are impaired for proteolysis, substrate-stimulated gating, and ATPase activity. Conclusion:The proteasome requires normal ATP binding for assembly and function. Significance: Protein substrates promote their own degradation by inducing ATP-dependent proteasome functions.

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Section: Discussionmentioning

confidence: 99%

ATP Binding by Proteasomal ATPases Regulates Cellular Assembly and Substrate-induced Functions of the 26 S Proteasome

Kim

Thompson

et al. 2013

Journal of Biological Chemistry

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“…Accordingly, proteasomes isolated from a yeast deletion strain lacking Rpn10, showed reduced levels of gate opening by Ub conjugates (9). However, the stimulation of peptide hydrolysis by Ub aldehyde was not decreased (Fig.…”

Section: Stimulation Of Yeast 26 S Atpases Requires Ubp6 But Not Itsmentioning

confidence: 99%

“…Ubiquitin Aldehyde with a Protein Substrate also Activates 26 S ATPases-It had been reported previously that free, unanchored Ub chains, similar to Ub aldehyde, can stimulate gate opening (9,10). Therefore, we tested whether linear Ub 6 chains, which stimulate gate opening, similar to Lys-48 chains ( Fig.…”

Section: Ubiquitin Conjugates Stimulate 26 S Proteasome Atpasementioning

confidence: 99%

Ubiquitinated Proteins Activate the Proteasomal ATPases by Binding to Usp14 or Uch37 Homologs

Peth

Kukushkin

Bossé³

et al. 2013

Journal of Biological Chemistry

147

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Background:The 26 S proteasome requires ATP hydrolysis to degrade ubiquitinated proteins. Results: Ubiquitin conjugates activate ATP hydrolysis, provided they contain loosely folded domains and their ubiquitin chains bind to the 26 S-associated DUBs. Conclusion: By stimulating ATP hydrolysis, ubiquitinated proteins induce their own degradation. Significance: Regulation of ATPase activity by Usp14 and Uch37 links proteolysis and deubiquitination and enhances the specificity of the proteasome for ubiquitin conjugates.

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“…The 20S proteasome purified from human spleen and erythrocytes (purchased from BioMol, Plymouth Meeting, PA) were in glycerol 50%. Yeast 20S proteasomes (supplemental Table S2) were purified by IgG Sepharose affinity protocol followed by a gel-filtration on Superose 6 column (PC 3.2/30, Amersham Biosciences, Uppsala, Sweden) (15).…”

Section: Smentioning

confidence: 99%

Driving Forces of Proteasome-catalyzed Peptide Splicing in Yeast and Humans

Mishto

Goede

Taube

et al. 2012

Molecular & Cellular Proteomics

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179

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Proteasome-catalyzed peptide splicing (PCPS) represents an additional activity of mammalian 20S proteasomes recently identified in connection with antigen presentation. We show here that PCPS is not restricted to mammalians but that it is also a feature of yeast 20S proteasomes catalyzed by all three active site ␤ subunits. No major differences in splicing efficiency exist between human 20S standard-and immuno-proteasome or yeast 20S proteasome. Using H 2 18 O to monitor the splicing reaction we also demonstrate that PCPS occurs via direct transpeptidation that slightly favors the generation of peptides spliced in cis over peptides spliced in trans. The 20S proteasome with its proteolytically active site ␤-subunits (␤1, ␤2, and ␤5) is a N-terminal nucleophilic hydrolase, widely conserved during evolution from yeast to mammals. It is the central proteolytic machinery of the ubiquitin proteasome system and the catalytic core of the 26S proteasome that is built by the association of 19S regulator complexes with the 20S proteasome. As part of the 26S proteasome the 20S core degrades poly-ubiquitylated proteins to peptides of 3 to 20 residues in length (1). A small percentage of these peptides is transported to the endoplasmic reticulum, bound by major histocompatibility complex (MHC) 1 class I molecules, and presented at the cell surface to CD8ϩ cytotoxic T lymphocyte for immune recognition. This antigen presentation pathway is usually restricted to the proteasome-dependent processing of self-and viral-proteins (2). Antigen presentation is generally increased after IFN-␥ stimuli because it induces, among others, the synthesis of alternative catalytic subunits (␤1i, ␤2i, and ␤5i) and the concomitant formation of immunoproteasomes (i-proteasomes) (2).All active ␤ subunits carry an N-terminal threonine residue as reactive nucleophile. Therefore, their distinct cleavage preferences are determined by the structural features of the substrate binding pockets. In particular, the nonprimed substrate binding site of the active site ␤ subunits binds the residues of the peptide substrate that are located at the N-terminal side of the cleaved residue. The residues of the peptide located C-terminally of the cleavage site are bound by the primed substrate binding site. The binding to both substrate binding sites of the active site ␤ subunit provides the stability and the orientation of the substrate, which is mandatory to carry out the proteolytic cleavage (3).Peptides can be produced by proteasomes during the degradation of proteins or polypeptides by conventional peptide bond hydrolysis or by proteasome-catalyzed peptide splicing (PCPS). The latter has been demonstrated in vivo so far only for four MHC class I-restricted epitopes (4 -8), leading to the assumption that PCPS is most likely a rare event that lacks any wider functional importance (9). PCPS was suggested to occur in a direct transpeptidation reaction, in either cis or trans, by linking two proteasomal cleavage products (PCPs) derived either from the same or from two ...

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Polyubiquitin substrates allosterically activate their own degradation by the 26S proteasome

Cited by 65 publications

References 34 publications

ATP Binding by Proteasomal ATPases Regulates Cellular Assembly and Substrate-induced Functions of the 26 S Proteasome

ATP Binding by Proteasomal ATPases Regulates Cellular Assembly and Substrate-induced Functions of the 26 S Proteasome

Ubiquitinated Proteins Activate the Proteasomal ATPases by Binding to Usp14 or Uch37 Homologs

Driving Forces of Proteasome-catalyzed Peptide Splicing in Yeast and Humans

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