Intrinsic disorder in ubiquitination substrates

Tzachi Hagai, Ariel Azia, Ágnes Tóth-Petróczy, Yaakov Levy

Research output: Contribution to journalArticlepeer-review


The ubiquitin-proteasome system is responsible for the degradation of numerous proteins in eukaryotes. Degradation is an essential process in many cellular pathways and involves the proteasome degrading a wide variety of unrelated substrates while retaining specificity in terms of its targets for destruction and avoiding unneeded proteolysis. How the proteasome achieves this task is the subject of intensive research. Many proteins are targeted for degradation by being covalently attached to a poly-ubiquitin chain. Several studies have indicated the importance of a disordered region for efficient degradation. Here, we analyze a data set of 482 in vivo ubiquitinated substrates and a subset in which ubiquitination is known to mediate degradation. We show that, in contrast to phosphorylation sites and other regulatory regions, ubiquitination sites 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 ubiquitination sites to be in disordered regions; however, a significant number is still found in ordered regions. Moreover, in many cases, disordered regions are absent from ubiquitinated substrates 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 ubiquitination may induce unfolding.

Original languageEnglish
Pages (from-to)319-324
Number of pages6
JournalJournal of Molecular Biology
Issue number3
StatePublished - 23 Sep 2011
Externally publishedYes


  • SUMOylation
  • acetylation
  • intrinsically disordered
  • proteasomal degradation
  • ubiquitination


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