# Structural and Functional Studies of Molecular Machines Involved in Chemical Modifications of Macromolecules

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2021 · $410,000

## Abstract

PROJECT SUMMARY / ABSTRACT
 Our lab focuses on structural and functional studies of molecular machines involved in chemical
modifications of macromolecules. Naturally occurring chemical modifications of macromolecules play essential
roles in all aspects of molecular biology, from transcriptional and translational regulation to functional modulation
of various proteins. Misregulation of the chemical modifications is involved in many human diseases such as
cancers and neurodegenerative diseases. Although many have been described and characterized, there are still
significant amounts of chemical modification systems that are poorly understood. Our long term goal is to
elucidate the structure and function of molecular machines involved in various chemical modification systems
and develop new tools and strategies to modulate their activity against the relevant diseases based on what we
have learned. In the next five years, we will be focusing on two systems, the p97 related ubiquitination system
and the Vault related ADP-ribosylation system.
 More than thirty mutations of human p97 have been identified, which are associated with a number of
neurodegenerative diseases. The molecular mechanism, however, remains elusive. Through structural biology
approaches and protein engineering, we will address 1) how p97 processes ubiquitin chains of different
topologies through the cofactors; 2) the structural and functional consequences of disease mutations; 3) the
mechanism of inhibitors of p97 and its cofactors. Our efforts promise unprecedented insights into the function of
p97, a central hub of cellular protein homeostasis.
 Vault is the largest ribonucleoprotein in eukaryotic cells with a unique structure. The function of Vault has
been linked to drug resistance in cancer and innate immune response. Recently, major vault protein (MVP) was
identified as one of the 9 marker genes that can predict influenza vaccination responses. Given the importance
of vaccine development during this COVID-19 pandemic, a deep understanding of Vault’s molecular mechanism
is critical. We are going to focus on PARP4, the only enzyme in the Vault complex catalyzing ADP-ribosylation.
Elucidating the function of PARP4 and how it interacts with Vault particle is the key to understand the molecular
function of Vault.

## Key facts

- **NIH application ID:** 10276853
- **Project number:** 1R35GM143052-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Minglei Zhao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2021-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276853

## Citation

> US National Institutes of Health, RePORTER application 10276853, Structural and Functional Studies of Molecular Machines Involved in Chemical Modifications of Macromolecules (1R35GM143052-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10276853. Licensed CC0.

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