Intrinsic Disorder in Ubiquitination Substrates

Abstract The ubiquitin– proteasomesystem is responsible for the degradation of numerous proteins in eukaryotes. Degradation is an essential process in many cellular pathways and involves the proteasomedegrading a wide variety of unrelated substrates while retaining specificity in terms of its targets for destruction and avoiding unneeded proteolysis. How the proteasomeachieves this task is the subject of intensive research. Many proteins are targeted for degradation by being covalently attached to a poly- ubiquitinchain. Several studies have indicated the importance of a disordered region for efficient degradation. Here, we analyze a data set of 482 in vivo ubiquitinatedsubstrates and a subset in which ubiquitinationis known to mediate degradation. We show that, in contrast to phosphorylation sites and other regulatory regions, ubiquitinationsites do not tend to be located in disordered regions and that a large number of substrates are modified at structured regions. In degradation-mediated ubiquitination, there is a significant bias of ubiquitinationsites to be in disordered regions; however, a significant number is still found in ordered regions . Moreover, in many cases, disordered regions are absent from ubiquitinatedsubstrates or are located far away from the modified region. These surprising findings raise the question of how these proteins are successfully unfolded and ultimately degraded by the proteasome. They indicate that the folded domain must be perturbed by some additional factor, such as the p97 complex, or that ubiquitinationmay induce unfolding.