The ubiquitin-mediated proteolytic pathway: mode of action and clinical implications.
Proteolysis via the ubiquitin system plays important roles in a variety of basic cellular processes. Among these are regulation of cell cycle and division, modulation of the immune and inflammatory responses, and development and differentiation. In all cases studied, these complex processes are mediated via degradation or processing of a single or a subset of specific proteins. Ubiquitin-mediated degradation of a protein involves two discrete and successive steps: (1) conjugation of multiple moieties of ubiquitin to the protein, and (2) degradation of the conjugated protein by the 26S proteasome complex with the release of free and reutilizable ubiquitin. In a few cases, it has been reported that ubiquitination targets membrane-anchored proteins to degradation in the lysosome/vacuole. An important yet largely unresolved problem involves the mechanisms that endow the system with the high degree specificity and selectivity toward its many substrates. These are determined by a large family of ubiquitin-protein ligases that recognize different primary and/or secondary/post-translational motifs in the different substrates and by a wide array of modifying enzymes, such as protein kinases, and ancillary proteins, such as molecular chaperones, that render them susceptible for recognition by the ligases via modification or association with protein substrates. With the broad spectrum of protein substrates and the complex enzymatic machinery involved in targeting them, it is not surprising that the system was recently implicated in the pathogenesis of several important diseases. In addition, genetic studies in animals underscore the role of the system in normal development. We briefly review the enzymatic cascade involved in ubiquitin-mediated degradation, describe some of the structural motifs identified by the conjugating machinery, and summarize recent developments in the involvement of the system in the pathogenesis of selected disease states.
Ciechanover
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Department of Biochemistry, Bruce Rappaport Faculty of Medicine and the Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Bat Galim, Haifa.
Orian
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Schwartz
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D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007107:Immune System / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*
D002352:Carrier Proteins; D009097:Multienzyme Complexes; D014452:Ubiquitins; C046288:ubiquitin carrier proteins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D008025:Ligases