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Coordination of chaperone interactions that dictate protein folding and trafficking

Award Number: R35GM133552
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: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Coordination of chaperone interactions that dictate protein folding and trafficking - PROJECT SUMMARY Proteins fold into their 3-dimensional shape with the help of chaperones and other protein folding factors, which together comprise the proteostasis network (PN). During the protein quality control process, transient binding interactions between individual client proteins and proteostasis factors mediate folding into native functional structures, thereby ensuring trafficking to the correct cellular destination or facilitating degradation of detrimental misfolded states. Consequently, imbalances in interactions between proteostasis factors and client proteins result in quality control defects that lead to diverse protein misfolding diseases, including highly prevalent neurodegenerative diseases such as Alzheimer’s and Parkinson’s Disease, and loss-of-function diseases such as Cystic Fibrosis. The folding, maturation, and trafficking of large multi-domain and multi-subunit proteins is a complex and highly client-specific process that depends on engaging the appropriate component of the PN at the correct time. Many proteostasis dependencies for individual client proteins are known, but little is understood about the engagement order and whether correct sequential interactions are required for proper folding and trafficking. We have utilized the power of chemical biology and quantitative proteomics to develop a new tool, time-resolved interactome profiling, to interrogate the dynamics of the interaction between disease-associated protein variants and the PN. We examined the coordination requirement of different proteostasis pathways as they affect protein secretion (thyroglobulin) and loss-of-function protein misfolding (cystic fibrosis transmembrance conductance regulator – CFTR). Loss of secretion of destabilized thyroglobulin variants, a thyroid prohormone, is a leading cause of congenital hypothyroidism while misfolding and pre-mature degradation of CFTR variants is the primary cause of Cystic Fibrosis. We have identified three projects that leverage the utility of our approach and build upon the groundwork laid by our previous findings. These include: 1) Determining the contribution of degradation factors to secretion loss of misfolded thyroglobulin variants. 2) Elucidating the proteostasis dynamics of divergent multipass membrane proteins, and 3) Enhancing the time-resolution of our time-resolved interactomics approach to capture early ER translocation and folding dynamics. Results from our studies will provide significant new insights into how the dynamics of protein folding and trafficking pathways can be manipulated therapeutically for disease intervention.


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: 2026 ( Subtotal = $427,729 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	7	1/15/2026	NON-COMPETING CONTINUATION	$427,729
														Subtotal = $427,729

Issue Date FY: 2025 ( Subtotal = $475,254 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	6	1/16/2025	COMPETING CONTINUATION	$475,254
2025	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	5	1/8/2025	NON-COMPETING CONTINUATION	$0
2025	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	002	5	5/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $475,254

Issue Date FY: 2023 ( Subtotal = $395,941 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	5	8/29/2023	NON-COMPETING CONTINUATION	$395,941
														Subtotal = $395,941

Issue Date FY: 2022 ( Subtotal = $637,023 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	4	7/28/2022	NON-COMPETING CONTINUATION	$395,941
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	001	4	8/12/2022	SUPPLEMENT FOR EXPANSION	$241,082
														Subtotal = $637,023

Issue Date FY: 2021 ( Subtotal = $395,941 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	3	7/5/2021	NON-COMPETING CONTINUATION	$395,941
														Subtotal = $395,941

Issue Date FY: 2020 ( Subtotal = $394,786 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	2	6/25/2020	NON-COMPETING CONTINUATION	$394,786
														Subtotal = $394,786

Issue Date FY: 2019 ( Subtotal = $394,786 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Biomedical Research and Research Training	000	1	8/22/2019	NEW	$394,786
														Subtotal = $394,786

Grand Total All Awards = $3,121,460

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Coordination of chaperone interactions that dictate protein folding and trafficking

Award Number: R35GM133552

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: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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