title: Ubiquitylation Directly Induces Fold Destabilization of Proteins.
abstract: Ubiquitin is a common post-translational modifier and its conjugation is a key signal for proteolysis by the proteasome. Because the molecular mass of ubiquitin is larger than that of other modifiers such as phosphate, acetyl, or methyl groups, ubiquitylation not only influences biochemical signaling, but also may exert physical effects on its substrate proteins by increasing molecular volume and altering shape anisotropy. Here we show that ubiquitylation destabilizes the fold of two proteins, FKBP12 and FABP4, and that elongation of the conjugated ubiquitin chains further enhances this destabilization effect. Moreover, NMR relaxation analysis shows that ubiquitylation induces characteristic structural fluctuations in the backbone of both proteins. These results suggest that the ubiquitylation-driven structural fluctuations lead to fold destabilization of its substrate proteins. Thus, physical destabilization by ubiquitylation may facilitate protein degradation by the proteasome.
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Morimoto
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.|Center for Medical Education, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Erik
authors.initials: E
authors.lastname: Walinda
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Fukada
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugase
authors.affiliation: Department of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto-Daigaku Katsura, Nishikyo-Ku, Kyoto 615-8510, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shirakawa
mesh_terms: D016880:Anisotropy; D002152:Calorimetry, Differential Scanning; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D011485:Protein Binding; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D040901:Proteomics; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry*; D013696:Temperature; D025801:Ubiquitin / Q000737:chemistry*; D054875:Ubiquitination
chemical_list: C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D022061:Tacrolimus Binding Protein 1A