# Decoding the regulation of protein folding by synonymous codon usage

> **NIH NIH DP1** · UNIVERSITY OF NOTRE DAME · 2022 · $1,095,500

## Abstract

PROJECT SUMMARY - Decoding the regulation of protein folding by synonymous codon usage
Synonymous mutations are widespread in complex, polygenic diseases but are typically regarded as
phenotypically silent, as they preserve the amino acid sequence of the encoded protein. Yet, synonymous
mutations can significantly perturb protein homeostasis through a variety of mechanisms, including perturbing
the folding mechanism of the encoded protein. Recently, my lab discovered that synonymous codon-induced
changes to protein folding can be large enough to (a) exceed the protein homeostatic buffering provided by
molecular chaperones and (b) lead to a dramatic two-fold decrease in cell growth rate. For these proteins,
changing the codon usage pattern produces a folded protein with an altered structure, which leads to changes
in activity and/or susceptibility to degradation by cellular proteases. The profound implication of these results is
that codon usage represents another level of information encoded within genomes, linking together “silent”
genetic differences with proper protein function and regulation of a potentially broad range of cellular
mechanisms. Historically, however, studying perturbations to protein folding mechanisms in vivo has presented
immense technical challenges. For this reason, to date only a few examples have been identified of connections
between codon usage and protein folding. As a result, we lack a comprehensive picture of the extent to which
synonymous codon usage contributes to the production of a functional proteome and how synonymous
mutations perturb protein homeostasis. This Pioneer Award project is designed to break through existing
technical challenges, developing a novel approach to (i) broadly measure for the first time the number and types
of proteins with folding mechanisms sensitive to synonymous codon usage, across an entire proteome and (ii)
deeply interrogate which codon usage patterns and features best support proper protein folding in vivo. The
ambitious, overarching goal of this project is to enable a next generation of genomic inference by developing a
predictive understanding of the synonymous codon usage patterns that best support production of a functional
proteome and the dysregulation that leads to human genetic disease.

## Key facts

- **NIH application ID:** 10488669
- **Project number:** 5DP1GM146256-02
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Patricia Louise Clark
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,095,500
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488669

## Citation

> US National Institutes of Health, RePORTER application 10488669, Decoding the regulation of protein folding by synonymous codon usage (5DP1GM146256-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10488669. Licensed CC0.

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