Human O-GlcNAcase (OGA) regulates a wide variety of essential biological processes by hydrolyzing O- GlcNAcylation from numerous proteins in response to nutrient and stress. Even though dysregulated OGA has been indicated in many diseases, little is known about how OGA's function is regulated. Dynamic function of OGA is mainly reflected by the changes of its substrate specificity, which is challenging to be characterized. One part of the challenge is the lack of information on OGA substrate recognition, as no apparent sequence motif can be defined in its substrate proteins. The other part of the challenge is the paucity of strategies to investigate OGA's substrate targeting and regulatory mechanism in cells. As a breakthrough in the field, we recently solved the first crystal structures of human OGA, revealing a unique structural feature that could contribute to substrate recognition. We propose to further characterize OGA's substrate specificity by solving new structures of OGA in complex with various substrates. We also propose to develop an innovative strategy to profile OGA's physiological substrates and binding partners in an effort to uncover the molecular signatures underlying the functional dysregulation of OGA in cancer development and programmed cell death. This study will provide unprecedented insights into the critical role of OGA in coupling O-GlcNAc biology to modulation of cell survival and death.

Public Health Relevance

O-GlcNAcase is an important human enzyme. Its aberrant function has been detected in a wide variety of diseases, such as Alzheimer's, diabetes, and many types of cancer. This application describes innovative structural and mechanistic studies to characterize the function and regulation of this enzyme to facilitate our understanding of disease and designing new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM126300-03
Application #
9773207
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Marino, Pamela
Project Start
2017-09-20
Project End
2021-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715