The 26S Proteasome

Abstract The 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: 3‐527‐30837‐8 The sections in this article are Introduction The 20S Proteasome Structure Enzyme Mechanism and Proteasome Inhibitors Immunoproteasomes The 26S Proteasome The Ubiquitin–Proteasome System Ultrastructure of the 26S Proteasome and Regulatory Complex The 19S Regulatory Complex ATPases of the RC The non‐ATPase Subunits Biochemical Properties of the Regulatory Complex Nucleotide Hydrolysis Chaperone‐like Activity Proteasome Activation Ubiquitin Isopeptide Hydrolysis Substrate Recognition Substrate Recognition by Proteasomes Degradation Signals (Degrons) Ubiquitin‐dependent Recognition of Substrates Substrate Selection Independent of Ubiquitin Proteolysis by the 26S Proteasome Presumed Mechanism Contribution of Chaperones to Proteasome‐mediated Degradation Substrate Binding to the 26S Proteasome Translocation of the Polypeptide Substrate to the Central Proteolytic Chamber Processing by the 26S Proteasome Proteasome Biogenesis Subunit Synthesis Biogenesis of the 20S Proteasome Biogenesis of the RC Post‐translational Modification of Proteasome Subunits Assembly of the 26S Proteasome Proteasome Activators REGs or PA28s REGs PA200 Hybrid Proteasomes ECM29 Protein Inhibitors of the Proteasome Physiological Aspects Tissue and Subcellular Distribution of Proteasomes Physiological Importance Conclusions