Ubiquitin and Ubiquitin‐like Protein Conjugation

Abstract Protein modification by ubiquitin and ubiquitin‐like proteins (Ubls) plays a pervasive role in eukaryotic cell regulation. One aim of this article is to survey the ubiquitin and Ubl conjugation systems in order to highlight key mechanistic and functional features. Another is to discuss some of the gaps in our understanding of both the evolutionary origins of these conjugation systems and the changes Ubl attachment can impart on a conjugated protein. The ubiquitin and Ubl systems use related enzymes to activate and attach ubiquitin and Ubls to proteins (and, in at least one case, to phospholipids). Most ubiquitin and Ubl attachments are dynamic, with efficient reversal of the modifications by a battery of deconjugating enzymes. The versatility of these systems is reflected in the enormous array of biological processes they control. It is likely that ubiquitin and Ubl attachments function fundamentally as a means of regulating macromolecular interactions. Best known is the ability of polyubiquitinated protein to bind with high affinity to polyubiquitin receptor sites on the proteasome, causing the rapid degradation of the tagged protein. Specific examples of physiological deployment of ubiquitin and Ubl attachment will be used to illustrate distinct mechanisms of regulation by these highly conserved protein modifiers. Originally published in: Protein Degradation, Volume 2. Edited by R. John Mayer, Aaron Ciechanover and Martin Rechsteiner. Copyright © 2005 Wiley‐VCH Verlag GmbH & Co. KGaA Weinheim. Print ISBN: 3‐527‐31130‐0 The sections in this article are Introduction The Ubiquitin Conjugation Pathway Ubiquitin Polymers Ubiquitin Attachment Dynamics Ubls: A Typical Modification Cycle by an Atypical Set of Modifiers Some Unusual Ubl Conjugation Features Origins of the Ubiquitin System Sulfurtransferases and Ubl Activation Enzymes The E1‐E2 Couple Ubiquitin‐binding Domains and Ubiquitin Receptors in the Proteasome Pathway A Proteasome “Ubiquitin Receptor” A Plethora of Ubiquitin‐binding Domains Ubiquitin‐Conjugate Adaptor Proteins Ubiquitin‐binding Domains and Membrane Protein Trafficking The MVB Pathway and RNA Virus Budding Sumoylation and SUMO‐binding Motifs A SUMO‐binding Motif A SUMO‐induced Conformational Change Interactions Between Different Sumoylated Proteins General Biochemical Functions of Protein‐Protein Conjugation Negative Regulation by Ubl Conjugation Positive Regulation by Ubl Conjugation Cross‐regulation by Ubls Conclusions Acknowledgments