Ubiquitin-proteasome system

Bajorek, Monika; Glickman, Michael S.

doi:10.1007/s00018-004-4131-y

Cited by 42 publications

(27 citation statements)

References 69 publications

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“…The 20S core without the regulatory particle is usually latent in cells because the N-termini of several α-subunits form a gate that most of the time blocks the entrance of substrates into the proteolytic chamber. Also, the core particle cannot recognize ubiquitin modifications or unfold protein substrates for degradation [24], [25]. However, in vivo the 20S core can degrade untagged proteins that are structurally unstable.…”

Section: Introductionmentioning

confidence: 99%

Altered Composition of Liver Proteasome Assemblies Contributes to Enhanced Proteasome Activity in the Exceptionally Long-Lived Naked Mole-Rat

et al. 2012

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The longest-lived rodent, the naked mole-rat (Bathyergidae; Heterocephalus glaber), maintains robust health for at least 75% of its 32 year lifespan, suggesting that the decline in genomic integrity or protein homeostasis routinely observed during aging, is either attenuated or delayed in this extraordinarily long-lived species. The ubiquitin proteasome system (UPS) plays an integral role in protein homeostasis by degrading oxidatively-damaged and misfolded proteins. In this study, we examined proteasome activity in naked mole-rats and mice in whole liver lysates as well as three subcellular fractions to probe the mechanisms behind the apparently enhanced effectiveness of UPS. We found that when compared with mouse samples, naked mole-rats had significantly higher chymotrypsin-like (ChT-L) activity and a two-fold increase in trypsin-like (T-L) in both whole lysates as well as cytosolic fractions. Native gel electrophoresis of the whole tissue lysates showed that the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous. Western blot analyses revealed that both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults. It thus appears that proteasomes in this species are primed for the efficient removal of stress-damaged proteins. Further characterization of the naked mole-rat proteasome and its regulation could lead to important insights on how the cells in these animals handle increased stress and protein damage to maintain a longer health in their tissues and ultimately a longer life.

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Section: Introductionmentioning

confidence: 99%

Altered Composition of Liver Proteasome Assemblies Contributes to Enhanced Proteasome Activity in the Exceptionally Long-Lived Naked Mole-Rat

et al. 2012

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“…These sites are present in a closed chamber sequestered from the general cellular environment. The proteolytic chamber is accessed through a pore that excludes folded protein domains but accommodates an unfolded or unstructured polypeptide (2,3). Regulatory and catalytic complexes must thus collaborate to degrade native proteins: the regulatory complex actively unfolds substrates containing structured domains and translocates them into the catalytic complex.…”

mentioning

confidence: 99%

Dependence of Proteasome Processing Rate on Substrate Unfolding

Henderson

Erales

Hoyt

et al. 2011

Journal of Biological Chemistry

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Protein degradation by eukaryotic proteasomes is a multistep process involving substrate recognition, ATP-dependent unfolding, translocation into the proteolytic core particle, and finally proteolysis. To date, most investigations of proteasome function have focused on the first and the last steps in this process. Here we examine the relationship between the stability of a folded protein domain and its degradation rate. Test proteins were targeted to the proteasome independently of ubiquitination by directly tethering them to the protease. Degradation kinetics were compared for test protein pairs whose stability was altered by either point mutation or ligand binding, but were otherwise identical. In both intact cells and in reactions using purified proteasomes and substrates, increased substrate stability led to an increase in substrate turnover time. The steadystate time for degradation ranged from ϳ5 min (dihydrofolate reductase) to 40 min (I27 domain of titin). ATP turnover was 110/min./proteasome, and was not markedly changed by substrate. Proteasomes engage tightly folded substrates in multiple iterative rounds of ATP hydrolysis, a process that can be ratelimiting for degradation.To degrade folded proteins, chambered protease complexes unfold substrates in an energy-dependent manner that requires two components (1). The first, a regulatory complex, recognizes substrates and initiates their processing. The second, an associated proteolytic complex, contains sites at which peptide bonds are hydrolyzed. These sites are present in a closed chamber sequestered from the general cellular environment. The proteolytic chamber is accessed through a pore that excludes folded protein domains but accommodates an unfolded or unstructured polypeptide (2, 3). Regulatory and catalytic complexes must thus collaborate to degrade native proteins: the regulatory complex actively unfolds substrates containing structured domains and translocates them into the catalytic complex. Substrate unfolding and translocation by bacterial ATP-dependent proteases has been extensively studied. It was found that substrate unfolding can be rate-limiting for degradation and that increased mechanical stability of substrates prolongs degradation (4). Is that also true of eukaryotic proteasomes? Studies from our laboratory (5, 6) and by others (7-10) are consistent with this conclusion, but studies using purified proteasomes and substrates of well-defined structure have been limited and have not determined the kinetic parameters associated with proteasome action.There are several requirements for rigorously performing such an analysis. Homogeneous substrates must be available that differ in their resistance to unfolding, but are otherwise identical in structure and proteasomal interaction. Most substrates are designated for destruction by the conjugation of ubiquitin chains, which provide a high affinity tag for proteasome association, but some substrates utilize alternate tags to designate degradation (11,12). Capture of ubiquitin chains and their...

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“…The gate is formed by N-terminal "tails" of subunits ( Fig. (3), structures (1), (2)) [50,51]. Deletion of the Nterminal sequence from the 3 subunit, which forms a crucial part of the gate, is sufficient to permanently open the gate and activate the yeast core particle [52].…”

Section: The Proteasome As An Allosteric Structurementioning

confidence: 99%

Allosteric Regulators of the Proteasome: Potential Drugs and a Novel Approach for Drug Design

Tan¹,

Osmulski²,

Gaczyńska³

2006

CMC

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The proteasome recently gained an exceptional attention as a novel drug target, therefore its inhibitors became important subjects for rational drug design. A synthetic competitive inhibitor Velcade was lately approved in a fast-track process to treat multiple myeloma and is tested with other types of cancers. The proteasome is a major proteolytic assembly in eukaryotic cells responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and apoptosis. The ubiquitin-proteasome pathway has been implicated in many diseases such as cancer, autoimmune diseases, inflammation, and stroke. The activity of the proteasome can be blocked for therapeutic purposes with competitive inhibitors like Velcade, which trigger apoptosis in target cells. However, much more versatile outcomes and a true control of the proteasome can be achieved with allosteric regulators. Certain natural proteins and peptides bind to the catalytic core of the proteasome and allosterically induce a wide array of effects ranging from changes in product size to substrate-specific inhibition. Designing small synthetic compounds allosterically interacting with the proteasome represents a novel approach that has enormous potential for the treatment of a wide range of diseases. Below we provide a review of current knowledge about proteasomal allosteric ligands.

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Ubiquitin-proteasome system

Cited by 42 publications

References 69 publications

Altered Composition of Liver Proteasome Assemblies Contributes to Enhanced Proteasome Activity in the Exceptionally Long-Lived Naked Mole-Rat

Altered Composition of Liver Proteasome Assemblies Contributes to Enhanced Proteasome Activity in the Exceptionally Long-Lived Naked Mole-Rat

Dependence of Proteasome Processing Rate on Substrate Unfolding

Allosteric Regulators of the Proteasome: Potential Drugs and a Novel Approach for Drug Design

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