Ubiquitin-independent proteolytic functions of the proteasome.
The discovery of the 20S proteasome (multicatalytic proteinase complex) was followed by the recognition that this multisubunit macromolecule is the proteolytic core of the 26S proteasome. Most of the research on extralysosomal proteolysis has concentrated on the role of the 26S proteasome in the ubiquitin-dependent proteolytic pathway. However, little attention has been directed toward the possible involvement of the proteasome in ubiquitin-independent proteolysis. In the past few years, many publications have provided evidence that both the 20S proteasome and the 26S proteasome can degrade some proteins in an ubiquitin-independent manner. Furthermore, it is becoming clear that demonstration of ubiquitin-protein conjugates after exposure of cells to proteasome inhibitors does not eliminate the possibility that the same protein can also be degraded by the proteasome without ubiquitination. The possible mechanisms of degradation of an unmodified protein by the 20S proteasome are discussed. These include targeting, protein unfolding, and opening of the gated channel to the catalytic sites. It is reasonable to assume that in the future the number of proteins recognized as substates of the ubiquitin-independent pathway will continue to increase, and that the metabolic significance of this pathway will be clarified.
Orlowski
Marian
M
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Wilk
Sherwin
S
D001669:Biochemical Phenomena; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D006868:Hydrolysis; D046911:Macromolecular Substances; D009097:Multienzyme Complexes / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis*; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011489:Protein Denaturation; D011506:Proteins; D015398:Signal Transduction; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism*
D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D011506:Proteins; D025801:Ubiquitin; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease