-
European Journal of Biochemistry Jun 1997A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key... (Review)
Review
A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutaryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a 'low-fuel' situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic alpha subunit, and beta and gamma subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.
Topics: AMP-Activated Protein Kinases; Amino Acid Sequence; Animals; Energy Metabolism; Molecular Sequence Data; Multienzyme Complexes; Protein Kinases; Protein Serine-Threonine Kinases; Sequence Homology, Amino Acid; Substrate Specificity
PubMed: 9208914
DOI: 10.1111/j.1432-1033.1997.00259.x -
Current Biology : CBProteasomes and related proteases are thought to be the principal machinery responsible for intracellular protein degradation. A new class of giant proteases has been... (Review)
Review
Proteasomes and related proteases are thought to be the principal machinery responsible for intracellular protein degradation. A new class of giant proteases has been discovered that can augment the catabolic functions of proteasomes and, under some conditions, may even substitute for proteasomes altogether.
Topics: Aminopeptidases; Cysteine Endopeptidases; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Endopeptidases; Image Processing, Computer-Assisted; Microscopy, Electron; Multienzyme Complexes; Proteasome Endopeptidase Complex; Thermoplasma
PubMed: 10469553
DOI: 10.1016/s0960-9822(99)80352-2 -
Journal of Biochemistry Jul 2003Modification of proteins by the covalent attachment of ubiquitin is a key regulatory mechanism of many cellular processes including protein degradation by the 26S... (Review)
Review
Modification of proteins by the covalent attachment of ubiquitin is a key regulatory mechanism of many cellular processes including protein degradation by the 26S proteasome. Deubiquitination, reversal of this modification, must also regulate the fate and function of ubiquitin-conjugated proteins. Deubiquitinating enzymes catalyze the removal of ubiquitin from ubiquitin-conjugated substrate proteins as well as from its precursor proteins. Deubiquitinating enzymes occupy the largest family of enzymes in the ubiquitin system, implying their diverse function in regulation of the ubiquitin-mediated pathways. Here we explore the diversity of deubiquitinating enzymes and their emerging roles as cellular regulators.
Topics: Animals; Cysteine Endopeptidases; Endopeptidases; Humans; Multienzyme Complexes; Transcription, Genetic; Ubiquitin Thiolesterase; Ubiquitins
PubMed: 12944365
DOI: 10.1093/jb/mvg107 -
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 -
Medicinal Research Reviews Jul 2001The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of... (Review)
Review
The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-proteasome pathway. In addition, this review covers the chemistry of synthetic and natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasome-mediated protein degradation in various intracellular processes, inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases.
Topics: Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Humans; Multienzyme Complexes; Proteasome Endopeptidase Complex; Ubiquitins
PubMed: 11410931
DOI: 10.1002/med.1009 -
The Journal of Biological Chemistry Apr 1998
Review
Topics: Acetylcysteine; Animals; Apoptosis; Cell Cycle; Cell Line; Cell Physiological Phenomena; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Mice; Multienzyme Complexes; Neurites; Neuroblastoma; Proteasome Endopeptidase Complex
PubMed: 9535824
DOI: 10.1074/jbc.273.15.8545 -
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 -
Cellular and Molecular Life Sciences :... Jul 2004The proteolytic active sites of the 26S proteasome are sequestered within the central chamber of its 20S catalytic core particle. Access to this chamber is through a... (Review)
Review
The proteolytic active sites of the 26S proteasome are sequestered within the central chamber of its 20S catalytic core particle. Access to this chamber is through a narrow channel defined by the outer alpha subunits. Free proteasome 20S core particles are found in an autoinhibited state in which the N-termini of neighboring alpha subunits are anchored by an intricate lattice of interactions blocking access to the channel. Entry of substrates into proteasomes can be enhanced by attachment of activators or regulatory particles. An important part of this activation is channel gating; regulatory particles rearrange the blocking residues to form an open pore and promote substrate entry into the proteolytic chamber. Interestingly, some substrates can open the entrance themselves and thus facilitate their own destruction. In this review, we will discuss the mechanisms proposed for channel gating and the interactions required to maintain stable closed and open conformations.
Topics: Amino Acid Sequence; Cysteine Endopeptidases; Humans; Molecular Sequence Data; Multienzyme Complexes; Proteasome Endopeptidase Complex; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 15224182
DOI: 10.1007/s00018-004-4131-y -
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 -
Biochimica Et Biophysica Acta May 2001Methanogenic archaea are dependent on sodium ions for methane formation. A sodium ion-dependent step has been shown to be methyl transfer from... (Review)
Review
Methanogenic archaea are dependent on sodium ions for methane formation. A sodium ion-dependent step has been shown to be methyl transfer from N(5)-methyltetrahydromethanopterin to coenzyme M. This exergonic reaction (DeltaG degrees '=-30 kJ/mol) is catalyzed by a Na(+)-translocating membrane-associated multienzyme complex composed of eight different subunits, MtrA-H. Subunit MtrA harbors a cob(I)amide prosthetic group which is methylated and demethylated in the catalytic cycle, demethylation being sodium ion-dependent. Based on the finding that in the cob(II)amide oxidation state the corrinoid is bound in a base-off/His-on configuration it is proposed that methyl transfer from MtrA to coenzyme M is associated with a conformational change of the protein and that this change drives the electrogenic translocation of the sodium ions.
Topics: Amino Acid Sequence; Archaeal Proteins; Bacterial Proteins; Cations, Monovalent; Cell Membrane; Corrinoids; Euryarchaeota; Methane; Methyltransferases; Models, Molecular; Molecular Sequence Data; Molecular Structure; Multienzyme Complexes; Porphyrins; Protein Conformation; Sodium
PubMed: 11248186
DOI: 10.1016/s0005-2728(00)00274-7