# Functional Analysis of O-GlcNAc Modifications Using Synthetic Protein Chemistry

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $325,875

## Abstract

   
DESCRIPTION (provided by applicant): "Functional Analysis of O-GlcNAc Modifications using Synthetic Protein Chemistry" O-GlcNAc modification (O-GlcNAcylation) is a dynamic protein-modification that is absolutely required for embryonic development in mammals, and is misregulated in diseases, including diabetes, neurodegeneration and cancer. Although approximately 1000 potential proteins are modified by O-GlcNAc, the effects of the vast majority of these modifications on protein function are completely unknown. This critical lack of knowledge exists in-part because traditional methods are deficient for the study of site-specific O-GlcNAcylation events. The long-term goal of our research program is to understand the consequences of O-GlcNAcylation on proteins that are key to human disease. The objectives of this application are to develop protein engineering strategies that uniquely enable the generation of proteins with site-specific O-GlcNAc modifications and to apply these methods to understand the effects of O-GlcNAcylation on the protein a-synuclein, the aggregation-prone protein in Parkinson's disease. Our preliminary studies demonstrate that homogeneously O-GlcNAcylated proteins can be prepared using synthetic chemistry. Furthermore, we have used synthetic protein chemistry to demonstrate that O-GlcNAcylation blocks a-synuclein aggregation. Guided by these preliminary studies, we will: 1) continue to develop general synthetic-strategies for the preparation of O-GlcNAcylated proteins, 2) investigate the molecular mechanism by which O-GlcNAcylation blocks a-synuclein aggregation and 3) determine the effects of O-GlcNAcylation on the cellular toxicity of a-synuclein. These studies are significant, as the effects of O-GlcNAcylation are almost completely unknown. Additionally, blocking a-synuclein aggregation is a key potential therapeutic strategy in Parkinson's disease. Our approach is also innovative as it enables the effects of O-GlcNAcylation to be directly tested in a
site-specific fashion and can be applied to other critical proteins in the future.

## Key facts

- **NIH application ID:** 9754837
- **Project number:** 5R01GM114537-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Matthew Robert Pratt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,875
- **Award type:** 5
- **Project period:** 2015-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9754837

## Citation

> US National Institutes of Health, RePORTER application 9754837, Functional Analysis of O-GlcNAc Modifications Using Synthetic Protein Chemistry (5R01GM114537-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9754837. Licensed CC0.

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