# Visualizing the Mechanisms of Protein Quality Control

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $73,133

## Abstract

Project Summary / Abstract
Optimal cellular function requires balanced networks that maintain protein synthesis, folding, trafficking,
remodeling and degradation. The Cdc48/p97/VCP AAA ATPase is an essential and abundant molecular
machine that helps maintain this balance across eukaryotic life and is therefore a critical control point for
proteostasis. Cdc48 is best characterized for its role in targeting ubiquitylated proteins for proteasomal
degradation, but the enzyme also functions in a wide range of other essential pathways, including cell cycle
progression, autophagy, membrane fusion, and gene expression. Mutations in human Cdc48 are causative of
a multisystem proteopathy that clinically manifests as a combination of Inclusion Body Myopathy, Paget's
Disease of Bone, Frontotemporal Dementia (collectively known as IBMPFD), and familial Amyotrophic Lateral
Sclerosis (fALS). Moreover, Cdc48 expression is elevated in several tumors and its inhibitors are an emerging
class of therapeutics for cancer treatment. Despite these critical roles, surprisingly little is known about the
molecular mechanisms that allow Cdc48 to perform its myriad cellular functions. More than thirty adaptors and
cofactors are known to interact with Cdc48, but how cells organize these binding partners into functional
complexes is also unknown. My research program aims to define the mechanisms underlying Cdc48 functions
by using an integrative approach of endogenous purification, proteomics, cryo-EM imaging, and computational
processing methods. Our approach will be used to visualize and characterize Cdc48 assemblies in an array of
its native compositional and conformational states. During the project period, we propose to achieve two major
goals: first, we aim to determine the molecular cues that functionally separate Cdc48 across multiple cellular
pathways; second, we seek to resolve how Cdc48 converts energy from ATP hydrolysis into a pulling force that
remodels and unfolds its protein substrates. Addressing these questions is essential to understand how Cdc48
drives a wide range of cellular processes and how its dysfunction and misregulation contribute to degenerative
disease and cancer. The tools we develop to accomplish these goals will likely be broadly applicable in
defining the structural landscapes of other challenging molecular machines.

## Key facts

- **NIH application ID:** 10574767
- **Project number:** 3R35GM133772-04S1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Peter Shen
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $73,133
- **Award type:** 3
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10574767

## Citation

> US National Institutes of Health, RePORTER application 10574767, Visualizing the Mechanisms of Protein Quality Control (3R35GM133772-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10574767. Licensed CC0.

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