# Deciphering protein ubiquitination with chemical biology tools

> **NIH NIH R35** · UNIVERSITY OF DELAWARE · 2024 · $385,786

## Abstract

Ubiquitination as a reversible post-translational modification is essential to a broad range of cellular
processes in humans. In addition to its function in proteasome-mediated protein degradation, ubiquitination is
crucial for many non-proteolytic cellular processes. These cellular processes are regulated by a diverse array of
polyubiquitin chains of different linkages and topologies, including recently discovered branched polyubiquitin
chains. Deubiquitinases (DUBs) modulate the ubiquitin chain linkage and structure and are considered promising
new targets for therapeutic intervention. The goals of our work are to investigate the recognition and cleavage
of atypical polyubiquitin chains and ubiquitinated proteins by DUBs; identify and characterize reader proteins of
branched ubiquitin chains and understand the roles of branched ubiquitin chains in mitophagy and receptor
endocytosis. These projects are interconnected and complementary to each other, building on our success in
chemical protein ubiquitination and DUB probe construction using semisynthetic approaches. The new chemical
biology tools developed, particularly novel activity-based DUB probes, will serve to unveil new biological targets
and functions in the ubiquitin system and provide new ways of identifying the reader and eraser proteins of
ubiquitin signals. The mechanistic and structural insights obtained will in turn propel drug discovery efforts
exploiting the ubiquitin system and lead to new opportunities and means for treating human diseases including
neurodegeneration and cancer.

## Key facts

- **NIH application ID:** 10765215
- **Project number:** 1R35GM152011-01
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Zhihao Zhuang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,786
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765215

## Citation

> US National Institutes of Health, RePORTER application 10765215, Deciphering protein ubiquitination with chemical biology tools (1R35GM152011-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10765215. Licensed CC0.

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