# Chemical proteomic mapping and functional manipulation of extracellular proteinaceous cysteines

> **NIH NIH R35** · NORTHWESTERN UNIVERSITY · 2024 · $389,995

## Abstract

Project Summary
Around 262,000 cysteine residues are intricately distributed throughout the human proteome. These cysteines
play pivotal roles in influencing protein folding, stability, enzymatic functions, and the response to oxidative stress.
Chemical probes designed to target cysteines are critical tools for investigating protein functionality and
advancing drug development. Chemical proteomics, particularly cysteine-directed activity-based protein profiling
(ABPP), has emerged as a fundamental technique for studying proteinaceous cysteines. ABPP employs a wide-
spectrum cysteine-reactive probe to effectively pinpoint cysteine sites across a variety of proteins, enabling
comprehensive functional exploration and facilitating ligand discovery. Traditionally, extracellular proteinaceous
cysteines have been largely neglected in the field of chemical proteomics. It was also believed that these
cysteines mainly formed disulfide bonds to stabilize protein structures. However, recent research has challenged
this notion by revealing the dynamic nature of extracellular redox environments, which can significantly influence
proteinaceous cysteine reactivity in the extracellular space. Consequently, a substantial knowledge gap remains
in identifying extracellular proteins containing unmodified, reactive cysteines in specific biological contexts. To
address this gap, this research program aims to establish an innovative chemical proteomic platform tailored for
mapping extracellular proteinaceous cysteines across a wide range of biological scenarios. These scenarios
include T cell activation, GGT5 genetic knockout, and various chemical treatments. Subsequently, we will
investigate the potential druggability of these extracellular proteinaceous cysteines. Finally, utilizing the insights
gained from targeting druggable extracellular proteinaceous cysteines, we aim to manipulate their functionality
in pursuit of two key outcomes: inducing cell-cell interactions and promoting targeted protein degradation.

## Key facts

- **NIH application ID:** 10938333
- **Project number:** 1R35GM154945-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Xiaoyu Zhang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $389,995
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938333

## Citation

> US National Institutes of Health, RePORTER application 10938333, Chemical proteomic mapping and functional manipulation of extracellular proteinaceous cysteines (1R35GM154945-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10938333. Licensed CC0.

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