Proteasome: a Nanomachinery of Creative Destruction

Kudriaeva, Anna; Belogurov, Alexey A.

doi:10.1134/s0006297919140104

Cited by 30 publications

(22 citation statements)

References 301 publications

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“…Preventing the formation of oligomerized and/or aggregated IDPs and oxidatively damaged proteins is the task of the proteasome through two major and complementary pathways: the ubiquitin dependent proteasome system (UPS) and the ubiquitin independent proteasome system (UIPS) [149,151,152,153,154,155].…”

Section: Intrinsically Disordered Proteinsmentioning

confidence: 99%

“…While both the UPS and UIPS may target IDPs for degradation (a specific example of UIPS targeting IDPs is p53 and p73 [187] and other evidence is available [191,192,193,194,195]), the UPS targets structured and misfolded proteins in need of removal, [151,196,197,198] whereas the UIPS is restricted to the removal of oxidatively damaged and disordered proteins.…”

Section: Proteasome Systemsmentioning

confidence: 99%

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Proteasome Activation to Combat Proteotoxicity

Jones

Tepe

2019

Molecules

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Loss of proteome fidelity leads to the accumulation of non-native protein aggregates and oxidatively damaged species: hallmarks of an aged cell. These misfolded and aggregated species are often found, and suggested to be the culpable party, in numerous neurodegenerative diseases including Huntington’s, Parkinson’s, Amyotrophic Lateral Sclerosis (ALS), and Alzheimer’s Diseases (AD). Many strategies for therapeutic intervention in proteotoxic pathologies have been put forth; one of the most promising is bolstering the efficacy of the proteasome to restore normal proteostasis. This strategy is ideal as monomeric precursors and oxidatively damaged proteins, so called “intrinsically disordered proteins” (IDPs), are targeted by the proteasome. This review will provide an overview of disorders in proteins, both intrinsic and acquired, with a focus on susceptibility to proteasomal degradation. We will then examine the proteasome with emphasis on newly published structural data and summarize current known small molecule proteasome activators.

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Section: Intrinsically Disordered Proteinsmentioning

confidence: 99%

Section: Proteasome Systemsmentioning

confidence: 99%

Proteasome Activation to Combat Proteotoxicity

Jones

Tepe

2019

Molecules

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“…Proteasomes are multicatalytic protease complexes that play a central role in cellular protein homeostasis by degrading damaged and misfolded proteins [ 1 – 3 ]. Within the cell, the majority of proteins destined to degradation are marked with ubiquitin and delivered to the proteasome, which cut them into peptide fragments that are then easily degraded by other proteases up to recoverably amino acids [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of CD8+ T cell epitopes through proteasome cleavage site predictions

et al. 2020

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Background We previously introduced PCPS (Proteasome Cleavage Prediction Server), a web-based tool to predict proteasome cleavage sites using n-grams. Here, we evaluated the ability of PCPS immunoproteasome cleavage model to discriminate CD8+ T cell epitopes. Results We first assembled an epitope dataset consisting of 844 unique virus-specific CD8+ T cell epitopes and their source proteins. We then analyzed cleavage predictions by PCPS immunoproteasome cleavage model on this dataset and compared them with those provided by a related method implemented by NetChop web server. PCPS was clearly superior to NetChop in term of sensitivity (0.89 vs. 0.79) but somewhat inferior with regard to specificity (0.55 vs. 0.60). Judging by the Mathew’s Correlation Coefficient, PCPS predictions were overall superior to those provided by NetChop (0.46 vs. 0.39). We next analyzed the power of C-terminal cleavage predictions provided by the same PCPS model to discriminate CD8+ T cell epitopes, finding that they could be discriminated from random peptides with an accuracy of 0.74. Following these results, we tuned the PCPS web server to predict CD8+ T cell epitopes and predicted the entire SARS-CoV-2 epitope space. Conclusions We report an improved version of PCPS named iPCPS for predicting proteasome cleavage sites and peptides with CD8+ T cell epitope features. iPCPS is available for free public use at https://imed.med.ucm.es/Tools/pcps/.

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“…Proteins including p97/Cdc48 [72,73], Hsp104 [65], Rix7 [68], archaeal VAT [66], and bacterial Clp [74] have been shown to act as translocases/unfoldases that can unfold a polypeptide chain by threading it through their central channel. Unfolding can serve as preparation for subsequent degradation of the polypeptide chain by proteases such as the proteasome [75,76]. By contrast, other AAA-ATPases act as segregases including mammalian N-ethyl maleimide sensitive factor (NSF) [77,78,79].…”

Section: Aaa-atpases In Ribosome Biogenesismentioning

confidence: 99%

Shaping the Nascent Ribosome: AAA-ATPases in Eukaryotic Ribosome Biogenesis

Prattes

Bergler

et al. 2019

Biomolecules

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AAA-ATPases are molecular engines evolutionarily optimized for the remodeling of proteins and macromolecular assemblies. Three AAA-ATPases are currently known to be involved in the remodeling of the eukaryotic ribosome, a megadalton range ribonucleoprotein complex responsible for the translation of mRNAs into proteins. The correct assembly of the ribosome is performed by a plethora of additional and transiently acting pre-ribosome maturation factors that act in a timely and spatially orchestrated manner. Minimal disorder of the assembly cascade prohibits the formation of functional ribosomes and results in defects in proliferation and growth. Rix7, Rea1, and Drg1, which are well conserved across eukaryotes, are involved in different maturation steps of pre-60S ribosomal particles. These AAA-ATPases provide energy for the efficient removal of specific assembly factors from pre-60S particles after they have fulfilled their function in the maturation cascade. Recent structural and functional insights have provided the first glimpse into the molecular mechanism of target recognition and remodeling by Rix7, Rea1, and Drg1. Here we summarize current knowledge on the AAA-ATPases involved in eukaryotic ribosome biogenesis. We highlight the latest insights into their mechanism of mechano-chemical complex remodeling driven by advanced cryo-EM structures and the use of highly specific AAA inhibitors.

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Proteasome: a Nanomachinery of Creative Destruction

Cited by 30 publications

References 301 publications

Proteasome Activation to Combat Proteotoxicity

Proteasome Activation to Combat Proteotoxicity

Identification of CD8+ T cell epitopes through proteasome cleavage site predictions

Shaping the Nascent Ribosome: AAA-ATPases in Eukaryotic Ribosome Biogenesis

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