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Current Biology : CB Jun 1998Proteasome assembly is regulated to ensure the enzyme is inactive until its active sites are compartmentalized within an interior aqueous chamber. In yeast, this depends... (Review)
Review
Proteasome assembly is regulated to ensure the enzyme is inactive until its active sites are compartmentalized within an interior aqueous chamber. In yeast, this depends on a dedicated chaperone that is trapped within the nascent proteasome, and degraded on maturation of the proteolytic subunits.
Topics: Animals; Cysteine Endopeptidases; Dimerization; Humans; Models, Biological; Molecular Chaperones; Multienzyme Complexes; Proteasome Endopeptidase Complex; Protein Folding
PubMed: 9651672
DOI: 10.1016/s0960-9822(98)70291-x -
Current Biology : CB Aug 1995The crystal structure of the proteasome suggests that degradation of ubiquitin-protein conjugates is achieved by unfolding the protein substrate and translocating it... (Review)
Review
The crystal structure of the proteasome suggests that degradation of ubiquitin-protein conjugates is achieved by unfolding the protein substrate and translocating it through a channel into a peptidase-containing chamber.
Topics: Biological Transport; Cysteine Endopeptidases; Hydrolysis; Multienzyme Complexes; Organelles; Proteasome Endopeptidase Complex; Protein Conformation; Protein Folding; Proteins; Saccharomyces cerevisiae; Thermoplasma; Ubiquitins
PubMed: 7583140
DOI: 10.1016/s0960-9822(95)00172-2 -
The Journal of Biological Chemistry Mar 1993
Review
Topics: Amino Acid Sequence; Animals; Biological Evolution; Cysteine Endopeptidases; Molecular Sequence Data; Multienzyme Complexes; Peptide Hydrolases; Proteasome Endopeptidase Complex; Protein Conformation; Sequence Homology, Amino Acid
PubMed: 8454582
DOI: No ID Found -
Genes To Cells : Devoted To Molecular &... Aug 1998Most cellular proteins are targeted for degradation by the proteasome, a eukaryotic ATP-dependent protease, after they have been covalently attached to ubiquitin (Ub) in... (Review)
Review
Most cellular proteins are targeted for degradation by the proteasome, a eukaryotic ATP-dependent protease, after they have been covalently attached to ubiquitin (Ub) in the form of a poly Ub chain functioning as a degradation signal. The proteasome is an unusually large multisubunit proteolytic complex, consisting of a central catalytic machine (called the 20S proteasome) and two terminal regulatory subcomplexes, termed PA700 or PA28, that are attached to both ends of the central portion in opposite orientations, to form enzymatically active proteasomes. The large assembled proteasome acts as a protein-destroying machine responsible for the selective breakdown of numerous ubiquitinylated cellular proteins and certain nonubiquitinylated proteins. To date, proteolysis mediated by the Ub-proteasome pathway has been shown to be involved in a wide variety of biologically important processes, such as the cell cycle, apoptosis, metabolism, signal transduction, immune response and protein quality control, implying that it functions as a previously unrecognized regulatory system for determining the final fate of protein factors involved in these biological reactions.
Topics: Adenosine Triphosphate; Cysteine Endopeptidases; Ligases; Models, Molecular; Multienzyme Complexes; Proteasome Endopeptidase Complex; Proteins; Ubiquitins
PubMed: 9797452
DOI: 10.1046/j.1365-2443.1998.00207.x -
Neuron Oct 2003The ubiquitin-proteasome system targets numerous cellular proteins for degradation. In addition, modifications by ubiquitin-like proteins as well as proteins containing... (Review)
Review
The ubiquitin-proteasome system targets numerous cellular proteins for degradation. In addition, modifications by ubiquitin-like proteins as well as proteins containing ubiquitin-interacting and -associated motifs modulate many others. This tightly controlled process involves multiple specific and general enzymes of the system as well as many modifying and ancillary proteins. Thus, it is not surprising that ubiquitin-mediated degradation/processing/modification regulates a broad array of basic cellular processes. Moreover, aberrations in the system have been implicated, either as a primary cause or secondary consequence, in the pathogenesis of both inherited and acquired neurodegenerative diseases. Recent findings indicate that the system is involved in the pathogenesis of Parkinson's, Alzheimer's, Huntington's, and Prion diseases as well as amyotrophic lateral sclerosis. This raises hopes for a better understanding of the pathogenetic mechanisms involved in these diseases and for the development of novel, mechanism-based therapeutic modalities.
Topics: Animals; Cysteine Endopeptidases; Humans; Multienzyme Complexes; Neurodegenerative Diseases; Proteasome Endopeptidase Complex; Signal Transduction; Ubiquitin
PubMed: 14556719
DOI: 10.1016/s0896-6273(03)00606-8 -
FEBS Letters Aug 1990There are continuing reports on the existence of complexes of sequential metabolic enzymes. New techniques for their detection have been described and include affinity... (Review)
Review
There are continuing reports on the existence of complexes of sequential metabolic enzymes. New techniques for their detection have been described and include affinity electrophoresis and the use of anti-idiotypic antibodies. Channeling of substrates has been reported for several systems as well as direct substrate transfer through dynamic enzyme associations. Kinetic parameters of metabolic control of organized systems have been formulated and tested in several systems. These recent results are expanding our understanding of metabolic processes and their control.
Topics: Biological Transport; Glycolysis; Kinetics; Multienzyme Complexes
PubMed: 2200717
DOI: 10.1016/0014-5793(90)81286-w -
The Journal of Biological Chemistry Sep 1982Using a three-step procedure designed to minimize the risks of proteolysis, high molecular weight complexes containing the same seven aminoacyl-tRNA synthetases specific... (Comparative Study)
Comparative Study
Using a three-step procedure designed to minimize the risks of proteolysis, high molecular weight complexes containing the same seven aminoacyl-tRNA synthetases specific for isoleucine, leucine, methionine, lysine, arginine, glutamic acid, and glutamine were purified from sheep liver and spleen, as well as from rabbit reticulocytes and liver. The polypeptide composition of these complexes, as revealed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, is characteristic of the animal species from which they are derived. The complexes from sheep liver and spleen display indistinguishable polypeptide patterns composed of 11 major components. Of the 10 common components which characterize the complexes of rabbit reticulocytes and liver, 4 are also shared by the complexes from sheep, while 6 have distinctly different electrophoretic mobilities. Furthermore, in the case of the complex from rabbit reticulocytes, it is shown that the enzyme and polypeptide composition of the complex is independent of the purification method employed. The isolation of high molecular weight complexes of identical aminoacyl-tRNA synthetase and polypeptide compositions from two cell types as radically different as rabbit reticulocytes and hepatocytes suggests that these multienzyme complexes do not arise as artifacts of preparation and supports the view that they reflect a structural organization existing within the cell.
Topics: Amino Acyl-tRNA Synthetases; Animals; Liver; Methionine-tRNA Ligase; Multienzyme Complexes; Rabbits; Reticulocytes; Sheep; Species Specificity
PubMed: 7107644
DOI: No ID Found -
Philosophical Transactions of the Royal... Sep 1999In eukaryotic cells, the vast majority of proteins in the cytosol and nucleus are degraded via the proteasome-ubiquitin pathway. The 26S proteasome is a huge protein... (Review)
Review
In eukaryotic cells, the vast majority of proteins in the cytosol and nucleus are degraded via the proteasome-ubiquitin pathway. The 26S proteasome is a huge protein degradation machine of 2.5 MDa, built of approximately 35 different subunits. It contains a proteolytic core complex, the 20S proteasome and one or two 19S regulatory complexes which associate with the termini of the barrel-shaped 20S core. The 19S regulatory complex serves to recognize ubiquitylated target proteins and is implicated to have a role in their unfolding and translocation into the interior of the 20S complex where they are degraded into oligopeptides. While much progress has been made in recent years in elucidating the structure, assembly and enzymatic mechanism of the 20S complex, our knowledge of the functional organization of the 19S regulator is rather limited. Most of its subunits have been identified, but specific functions can be assigned to only a few of them.
Topics: Adenosine Triphosphatases; Animals; Cysteine Endopeptidases; Humans; Multienzyme Complexes; Peptide Hydrolases; Proteasome Endopeptidase Complex; Proteins
PubMed: 10582236
DOI: 10.1098/rstb.1999.0494 -
ELife Nov 2016Respirasomes are macromolecular assemblies of the respiratory chain complexes I, III and IV in the inner mitochondrial membrane. We determined the structure of...
Respirasomes are macromolecular assemblies of the respiratory chain complexes I, III and IV in the inner mitochondrial membrane. We determined the structure of supercomplex IIIIIV from bovine heart mitochondria by cryo-EM at 9 Å resolution. Most protein-protein contacts between complex I, III and IV in the membrane are mediated by supernumerary subunits. Of the two Rieske iron-sulfur cluster domains in the complex III dimer, one is resolved, indicating that this domain is immobile and unable to transfer electrons. The central position of the active complex III monomer between complex I and IV in the respirasome is optimal for accepting reduced quinone from complex I over a short diffusion distance of 11 nm, and delivering reduced cytochrome to complex IV. The functional asymmetry of complex III provides strong evidence for directed electron flow from complex I to complex IV through the active complex III monomer in the mammalian supercomplex.
Topics: Animals; Cattle; Cryoelectron Microscopy; Electron Transport; Mitochondria; Multienzyme Complexes; Myocardium
PubMed: 27830641
DOI: 10.7554/eLife.21290 -
Nature Jun 2019Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses...
Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 Å. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.
Topics: Cryoelectron Microscopy; Deubiquitinating Enzymes; Glycine Hydroxymethyltransferase; HEK293 Cells; Humans; Inflammation; Interferon Type I; Models, Molecular; Multienzyme Complexes; Mutation; Protein Binding; Protein Multimerization; Protein Structure, Quaternary; Pyridoxal Phosphate; Signal Transduction
PubMed: 31142841
DOI: 10.1038/s41586-019-1232-1