# Visualizing the Mechanisms of Protein Quality Control

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $421,960

## Abstract

Optimal cellular function requires balanced networks that maintain a proper flux of protein synthesis, folding,
trafficking, remodeling and degradation. There are many conserved and abundant multi-component enzyme
complexes that directly support this balance across eukaryotic life and are therefore critical control points for
maintaining proteostasis. During the project period, we propose to achieve three major goals, each of which
addresses an important, yet distinct, component of proteostasis: first, we will determine how the Cdc48 AAA+
ATPase resolves translational stress by working with the Ribosome Quality Control complex to remove stalled
products of translation; second, we aim to determine the mechanisms of how the CCT chaperone machine
facilitates the co-translational folding of native protein substrates; and third, we will determine how Cdc48
works with multiple adaptor proteins to facilitate protein unfolding prior to their targeted degradation. Each of
these complexes are critical to maintaining cellular health, and their misregulation directly causes a variety of
degenerative phenotypes. In order to meet our proposed goals, my lab will employ an integrative, “lysate-to-
grid” approach that combines endogenous purifications, proteomics, cryo-EM imaging, and computational
processing to visualize the mechanisms of protein quality control machinery in their functional states. This
approach will enable us to understand the atomic-scale details of the continuous motions that underlie the
fundamental cellular processes of protein synthesis, folding, and unfolding, including how incomplete products
of translation are extracted from stalled ribosomes, how chaperones fold proteins as they are translated, and
how folded proteins overcome their energetic barriers to become unfolded prior to their degradation. Overall,
the insights we uncover will deepen understanding of how cells maintain proteostasis and how disruptions in
protein quality control machinery contribute to cellular dysfunction.

## Key facts

- **NIH application ID:** 10842569
- **Project number:** 2R35GM133772-06
- **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:** 2024
- **Award amount:** $421,960
- **Award type:** 2
- **Project period:** 2019-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842569

## Citation

> US National Institutes of Health, RePORTER application 10842569, Visualizing the Mechanisms of Protein Quality Control (2R35GM133772-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10842569. Licensed CC0.

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