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Decoding the regulation of protein folding by synonymous codon usage

Award Number: DP1GM146256
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Decoding the regulation of protein folding by synonymous codon usage - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,095,500 )
2025	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Trans-NIH Research Support	000	5	7/24/2025	NON-COMPETING CONTINUATION	$1,095,500
														Subtotal = $1,095,500

Issue Date FY: 2024 ( Subtotal = $1,095,500 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Trans-NIH Research Support	000	4	7/29/2024	NON-COMPETING CONTINUATION	$1,095,500
														Subtotal = $1,095,500

Issue Date FY: 2023 ( Subtotal = $1,095,500 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Trans-NIH Research Support	000	3	9/15/2023	NON-COMPETING CONTINUATION	$1,095,500
														Subtotal = $1,095,500

Issue Date FY: 2022 ( Subtotal = $1,095,500 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Trans-NIH Research Support	000	2	7/29/2022	NON-COMPETING CONTINUATION	$1,095,500
														Subtotal = $1,095,500

Issue Date FY: 2021 ( Subtotal = $1,095,500 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Trans-NIH Research Support	000	1	9/14/2021	NEW	$1,095,500
														Subtotal = $1,095,500

Grand Total All Awards = $5,477,500

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Decoding the regulation of protein folding by synonymous codon usage

Award Number: DP1GM146256

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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