The 26S Proteasome

Abstract

AbstractThe 26S proteasome is a large ATP‐dependent protease composed of more than 30 different polypeptide chains. Like the ribosome, the 26S proteasome is assembled from two “subunits”, the 19S regulatory complex and the 20S proteasome. The 19S regulatory complex confers the ability to recognize and unfold protein substrates, and the 20S proteasome provides the proteolytic activities needed to degrade the substrates. The 26S proteasome is the only enzyme known to degrade ubiquitylated proteins, and it also degrades intracellular proteins that have not been marked by ubiquitin. The 26S proteasome is located in the nucleus and cytosol of eukaryotic cells, where the enzyme is responsible for the selective degradation of a vast number of important cellular proteins. Because rapid proteolysis is a pervasive regulatory mechanism, the 26S proteasome is essential for the proper functioning of many physiological processes.Originally published in: Protein Degradation, Volume 1. Edited by R. John Mayer, Aaron Ciechanover and Martin Rechsteiner. Copyright © 2005 Wiley‐VCH Verlag GmbH & Co. KGaA Weinheim. Print ISBN: 3‐527‐30837‐8The sections in this article areIntroductionThe 20S ProteasomeStructureEnzyme Mechanism and Proteasome InhibitorsImmunoproteasomesThe 26S ProteasomeThe Ubiquitin–Proteasome SystemUltrastructure of the 26S Proteasome and Regulatory ComplexThe 19S Regulatory ComplexATPases of the RCThe non‐ATPase SubunitsBiochemical Properties of the Regulatory ComplexNucleotide HydrolysisChaperone‐like ActivityProteasome ActivationUbiquitin Isopeptide HydrolysisSubstrate RecognitionSubstrate Recognition by ProteasomesDegradation Signals (Degrons)Ubiquitin‐dependent Recognition of SubstratesSubstrate Selection Independent of UbiquitinProteolysis by the 26S ProteasomePresumed MechanismContribution of Chaperones to Proteasome‐mediated DegradationSubstrate Binding to the 26S ProteasomeTranslocation of the Polypeptide Substrate to the Central Proteolytic ChamberProcessing by the 26S ProteasomeProteasome BiogenesisSubunit SynthesisBiogenesis of the 20S ProteasomeBiogenesis of the RCPost‐translational Modification of Proteasome SubunitsAssembly of the 26S ProteasomeProteasome ActivatorsREGs or PA28sREGsPA200Hybrid ProteasomesECM29Protein Inhibitors of the ProteasomePhysiological AspectsTissue and Subcellular Distribution of ProteasomesPhysiological ImportanceConclusions