2002 Fiscal Year Final Research Report Summary
Studies on cellular basis of the endoplasmic reticulum-associated degradation and intracellular aggregation of misfolded proteins
| Project/Area Number |
13680695
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Structural biochemistry
|
|---|
| Research Institution | Osaka City University (2002)
Himeji Institute of Technology (2001) |
|---|
Principal Investigator |
TOKUNAGA Fuminori Osaka City University, Graduate School of Medicine, Associated Professor, 大学院・医学研究科, 助教授 (00212069)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KOIDE Takehiko Himeji Institute of Technology, Department of Life Science, Professor, 大学院・理学研究科, 教授 (60018695)
|
|---|
| Project Period (FY) |
2001 – 2002
|
| Keywords | ERAD / proteasome / N-linked oligosaccharide / ubiquitin ligase |
|---|
| Research Abstract |
The endoplasmic reticuium (ER) is known to function as a quality control machinery of nascent proteins, and various misfolded or unassembled proteins in the ER are targeted to ubiquitin/proteasome-mediated degradation after retrotranslocation to the cytosol through the Sec61 translocon. We have shown that not only proteasome inhibitors such as lactacystin and carbobenzoxy-leucyl-leucyl-leucinal (LLL), but also inhibitors of ER mannosidase I such as kifunensine and deoxyrnannojirimycin, strongly inhibit the ERAD of various misfolded proteins, suggesting that processing of N-linked oligosaccharide plays an important role on ERAD. In this study, collaborating with Dr. Yoshida in Tokyo Metropolitan Institute of Medical Science, we found that N-glycan serves as a signal for degradation by the Skpl-Cullin1-Fbx2-Rbx1 (SCF^<Fbx2>) ubiquitin ligase complex. The F-box protein Fbx2 binds specifically to proteins attached to N-inked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins. In addition, expression of the mutant Fbx2ΔF, which lacks the F-box domain that is essential for forming the SCF complex, appreciably blocks degradation of typical substrates of the ERAD pathway. Our results indicate that SCF^<Fbx2> ubiquitinates N-glycosylated proteins that are translocated from the ER to the cytosol by the quality control mechanism.
|
Research Products
(10 results)
-
-
-
-
-
-
-
[Publications] Yamanaka, K., Ishikawa, H., Megumi, Y., Tokunaga, F., Kanie, M., Rouault, T.A., Morishima, I., Minato, N., Ishimori, K., and Iwai, K.: "Identification of the Ubiquitin-protein Ligase that Recognizes Oxidized IRP2"Nature Cell Biol.. 5. 336-340 (2003)
Description
「研究成果報告書概要(欧文)」より
-
-
-
[Publications] Yoshida, Y., Chiba, T., Tokunaga, F., Kawasaki, H., Iwai, K., Suzuki, T., Ito, Y., Matsuoka, K., Yoshida, M.,Tanaka, K., and Tai T.: "E3 ubiquitin ligase that recognizes sugar chains."Nature. 418. 438-442 (2002)
Description
「研究成果報告書概要(欧文)」より
