Ubiquitin not only serves as a tag but also assists degradation by inducing protein unfolding.
Protein ubiquitination controls the cellular fate of numerous eukaryotic proteins. Despite its importance, many fundamental questions remain regarding its mechanism. One such question is how ubiquitination alters the biophysical properties of the modified protein and whether these alterations are significant in the cellular context. In this study, we investigate the effects of ubiquitination on the folding thermodynamics and mechanism of various substrates using computational tools and find that ubiquitination changes the thermal stability of modified proteins in a manner relevant to cellular processes. These changes depend on the substrate modification site and on the type of ubiquitination. Ubiquitination of the substrate Ubc7 at the residues that are modified in vivo prior to proteasomal degradation uniquely results in significant thermal destabilization and a local unwinding near the modification site, which indicates that ubiquitination possibly facilitates the unfolding process and improves substrate degradation efficiency. With respect to the substrate p19(4inkd), our results support a synergetic effect of ubiquitination and phosphorylation on the degradation process via enhanced thermal destabilization. Our study implies that, in addition to its known role as a recognition signal, the ubiquitin attachment may be directly involved in the cellular process it regulates by changing the biophysical properties of the substrate.
Hagai
Tzachi
T
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Levy
Yaakov
Y
D055592:Biophysical Phenomena; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D017510:Protein Folding; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination
D050764:Cyclin-Dependent Kinase Inhibitor p19; D011506:Proteins; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes