Mammalian 26S Proteasomes Remain Intact during Protein Degradation

Kriegenburg, Franziska; Seeger, Michael; Saeki, Yasushi; Tanaka, Keiji; Lauridsen, Anne-Marie B.; Hartmann‐Petersen, Rasmus; Hendil, Klavs B.

doi:10.1016/j.cell.2008.08.032

Cited by 36 publications

(26 citation statements)

References 63 publications

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“…The subunit Rpn10, which serves as a receptor for poly-ubiquitylated protein substrates, was assigned with stabilizing functions [127,128]. Consistent with this finding, RP-CP assemblies are stable entities during the degradation of protein substrates, because premature RP-CP dissociation might result in the release of toxic peptide intermediates produced by interrupted protein degradation.…”

Section: Regulation Of Rp-cp Assemblysupporting

confidence: 66%

Proteasome assembly

Enenkel

2014

Cell. Mol. Life Sci.

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In eukaryotic cells, proteasomes are highly conserved protease complexes and eliminate unwanted proteins which are marked by poly-ubiquitin chains for degradation. The 26S proteasome consists of the proteolytic core particle, the 20S proteasome, and the 19S regulatory particle, which are composed of 14 and 19 different subunits, respectively. Proteasomes are the second-most abundant protein complexes and are continuously assembled from inactive precursor complexes in proliferating cells. The modular concept of proteasome assembly was recognized in prokaryotic ancestors and applies to eukaryotic successors. The efficiency and fidelity of eukaryotic proteasome assembly is achieved by several proteasome-dedicated chaperones that initiate subunit incorporation and control the quality of proteasome assemblies by transiently interacting with proteasome precursors. It is important to understand the mechanism of proteasome assembly as the proteasome has key functions in the turnover of short-lived proteins regulating diverse biological processes.

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Section: Regulation Of Rp-cp Assemblysupporting

confidence: 66%

Proteasome assembly

Enenkel

2014

Cell. Mol. Life Sci.

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“…The CTH of Rpn10, carrying the ubiquitin-interacting motif (UIM) is alone responsible for this compensatory function, suggesting that in its extraproteasomal state the UIM of Rpn10 might mask the UBL domain of Dsk2, competing in this way with the interaction of Dsk2 with the proteasome. However, the presumed extraproteasomal shuttling of the proteasomal polyubiquitin receptor is questioned by the observation that human 26S proteasomes degraded polyubiquitylated Sic1 and c-IAP1 proteins in vitro without dissociating into the RP and CP and releasing any subunit (Kriegenburg et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Developmental-stage-specific regulation of the polyubiquitin receptors inDrosophila melanogaster

Lipinszki

Kiss

Pál

et al. 2009

Journal of Cell Science

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Recognition of polyubiquitylated substrates by the proteasome is a highly regulated process that requires polyubiquitin receptors. We show here that the concentrations of the proteasomal and extraproteasomal polyubiquitin receptors change in a developmentally regulated fashion. The stoichiometry of the proteasomal p54/Rpn10 polyubiquitin receptor subunit, relative to that of other regulatory particle (RP) subunits falls suddenly at the end of embryogenesis, remains low throughout the larval stages, starts to increase again in the late third instar larvae and remains high in the pupae, adults and embryos. A similar developmentally regulated fluctuation was observed in the concentrations of the Rad23 and Dsk2 extraproteasomal polyubiquitin receptors. Depletion of the polyubiquitin receptors at the end of embryogenesis is due to the emergence of a developmentally regulated selective proteolytic activity. To follow the fate of subunit p54/Rpn10 in vivo, transgenic Drosophila melanogaster lines encoding the N-terminal half (NTH), the C-terminal half (CTH) or the full-length p54/Rpn10 subunit were established in the inducible Gal4-UAS system. The daughterless-Gal4-driven whole-body expression of the full-length subunit or its NTH did not produce any detectable phenotypic changes, and the transgenic products were incorporated into the 26S proteasome. The transgene-encoded CTH was not incorporated into the 26S proteasome, caused third instar larval lethality and was found to be multi-ubiquitylated. This modification, however, did not appear to be a degradation signal because the half-life of the CTH was over 48 hours. Accumulation of the CTH disturbed the developmentally regulated changes in subunit composition of the RP and the emergence of the selective proteolytic activity responsible for the depletion of the polyubiquitin receptors. Build-up of subunit p54/Rpn10 in the RP had already started in 84-hour-old larvae and reached the full complement characteristic of the non-larval developmental stages at the middle of the third instar larval stage, just before these larvae perished. Similar shifts were observed in the concentrations of the Rad23 and Dsk2 polyubiquitin receptors. The postsynthetic modification of CTH might be essential for this developmental regulation, or it might regulate an essential extraproteasomal function(s) of subunit p54/Rpn10 that is disturbed by the expression of an excess of CTH.

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“…Biochemical methods and EM have been used to propose a model of allosterically driven disassembly of the 26S, controlled by ATP hydrolysis and correlating with the catalytic cycle (6). This model remains controversial, and results of a distinct set of experiments under different conditions failed to support it (74). However, the idea of periodic lowering of the affinity between the core and the cap may still be viable.…”

Section: Afm Is An Excellent Technique To Study Protein Dynamicsmentioning

confidence: 99%

Harnessing Proteasome Dynamics and Allostery in Drug Design

Gaczyńska

Osmulski

2014

Antioxidants & Redox Signaling

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Significance: The proteasome is the essential protease that is responsible for regulated cleavage of the bulk of intracellular proteins. Its central role in cellular physiology has been exploited in therapies against aggressive cancers where proteasome-specific competitive inhibitors that block proteasome active centers are very effectively used. However, drugs regulating this essential protease are likely to have broader clinical usefulness.

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Mammalian 26S Proteasomes Remain Intact during Protein Degradation

Cited by 36 publications

References 63 publications

Proteasome assembly

Proteasome assembly

Developmental-stage-specific regulation of the polyubiquitin receptors inDrosophila melanogaster

Harnessing Proteasome Dynamics and Allostery in Drug Design

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