Most of the current research on polyubiquitination is focused on its role in targeting tagged proteins to the 26S proteasome for degradation. Although it has been established that many polyubiquitinated proteins do not get degraded and become directly regulated by ubiquitination, the molecular mechanism of proteolysis-independent ubiquitination remains poorly understood. Ubiquitination of the yeast transcription factor Met4 by the SGF-Met30 ubiquitin ligase leads to inactivation of Met4 activity without its degradation. This proposal aims to use the SCFMet30/Met4 system as a model to gain insight into proteolysis-independent regulation by ubiquitin. Quantitative mass spectrometry will be performed to identify proteins that are responsible for the ubiquitin-mediated repression of Met4. Results from these studies will be complemented by experiments designed to relate the dimeric state of Met4 to its activation status. A large scale, proteome- wide strategy is also proposed to isolate novel ubiquitinated proteins that are regulated in a non-proteolytic manner. Insights gained from this investigation into proteolysis-independent ubiquitination will be of general interest to biomedical research as they will undoubtedly provide mechanistic detail into a lesser known function of ubiquitin. And since aspects of the ubiquitin system are often involved in human disease, these findings can provide insight into approaches relevant to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM082125-03
Application #
7671506
Study Section
Special Emphasis Panel (ZRG1-F08-G (20))
Program Officer
Carter, Anthony D
Project Start
2007-09-01
Project End
2010-12-01
Budget Start
2009-09-01
Budget End
2010-12-01
Support Year
3
Fiscal Year
2009
Total Cost
$51,710
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Yen, James L; Flick, Karin; Papagiannis, Christie V et al. (2012) Signal-induced disassembly of the SCF ubiquitin ligase complex by Cdc48/p97. Mol Cell 48:288-97