| Co-Investigator(Kenkyū-buntansha) |
YAMASHITA Yoshinori Tokyo Institute, Kyowo Hakko Inc. Researcher, 東京研究所, 主任研究員(研究職)
NAKAYAMA Keiko Faculty of Medicine, Tohoku University, Professor, 大学院・医学系研究科, 教授 (60294972)
NAKAYAMA Keiichi Kyushu University, Medical Institute of Bioregulation, Professor, 生体防御医学研究所, 教授 (80291508)
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| Research Abstract |
Intracellular protein degradation is involved in the regulation of biologically important phenomenon including cell cycle, transcriptional regulation and signal transduction. Ubiquitylation is mediated by a multienzyme cascade and involves the formation by ubiquitin of thiol esters with at least two, and, in most instances, three, distinct types of enzyme: an E1, an E2, and an E3.Then Polyubiquitylated proteins are recognized and degraded by proteasomes. In this cascade, E3 enzymes are thought to determine the substrate specificity of ubiquitylation and have been classified into two families, the HECT and RING-finger families.
The prototype U-box protein, yeast Ufd2, was identified as a ubiquitin-chain assembly factor (E4) that cooperates with a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3) to catalyze ubiquitin chain formation on artificial substrates. The U-box is a domain of -70 amino acids that is present in proteins from
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yeast to humans. We have reported that six mammalian U-box proteins have now been shown to mediate polyubiquitiylation in the presence of E1 and E2 and in the absence of E3. These data may suggest that U-box proteins constitute a third family of E3 enzymes. Almost U-box proteins interact with molecular chaperones, indicating that U-box type E3 is likely to be a chaperone-dependent E3. To deal with the accumulation of abnormal proteins, molecular chaperones refold abnormal proteins and U-box type E3 seems lo degrade misfolded proteins.
Machado-Joseph disease (MJD) is caused by expansion of a polyglutamine tract in the protein MJD1 and this form of MJD1 proteins accumulates in neuron and cause neuronal dysfunction. We have reported that one of the mammalian U-box protein. UFD2a mediated polyubiquitylation of MJD1. We reported that other U-box protein CHIP also is related to Parkinson's disease. We are on going to establish the therapeutic method for neurodegenerative diseases with U-box type E3. Less
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