Tuesday, July 1, 2025 7/1/2025

The role of the free energy landscape in Parkin's function and dysfunction in health and disease

Award Number: R01GM129076
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: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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The role of the free energy landscape in Parkin's function and dysfunction in health and disease - The RING ubiquitin E3 ligases are a superfamily of proteins critical to protein homeostasis and signaling in eukaryotes. Dysfunctions in E3 ligases are implicated in innumerable human diseases. This proposal focuses on the regulation of the ubiquitin E3 ligase Parkin. Parkin is central to the controlled destruction of damaged mitochondria by autophagy (mitophagy). Controlled mitophagy is particularly essential to cardiac and neuronal health. Uncontrolled mitophagy due to mutations in Parkin is clearly a driver of early onset Parkinson's disease (eoPD). Parkin is now implicated in a number of other neurological diseases, cardiomyopathy and in various cancers. The central goal here is to create an understanding the physical basis for regulation of Parkin and how clinically observed mutations promote unregulated activity leading to inadequately controlled mitophagy and other biological defects. Though much is known about the biology and structural basis of Parkin function, very little is certain about the physical basis for its regulation. Parkin activity is suppressed by its intra-molecular association with a ubiquitin-like domain and is allosterically activated by the binding of phosphorylated ubiquitin (pUb). Phosphorlyation of the Ubl domain also promotes activation. This complicated intersection of regulatory mechanisms can only be understood by the rigorous dissection of the underlying thermodynamics. Without this knowledge one cannot fully interpret the effects of mutations that lead to disease. We shall take advantage of the broad foundation of knowledge of the biology of Parkin and structural basis of its function to address the poorly understood thermodynamics of allosteric regulation of Parkin. The basis for regulatory control of Parkin will be cast in a modern statistical thermodynamics description of the protein ensemble. The influence of allosteric regulators and post-translational modifications will be examined by comprehensive hydrogen exchange monitored by mass spectrometry and NMR spectroscopy; advanced NMR relaxation techniques; single molecule fluorescence; calorimetry; enzymology; and mutagenesis. A more rigorous and complete understanding of the regulation of Parkin will enable a robust interpretation of pathological mutations. Not all pathological mutations can be simply explained as mutations that disrupt the levels of protein or mutations that directly impact the catalytic site. Examples of common pathological mutations will be examined to reveal the basis for their effects on Parkin's regulatory fidelity, with a longer- range goal of determining how this impact might be mitigated by small molecule 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: 2025 ( Subtotal = -$754 )
2025	2023	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	4	6/24/2025	NON-COMPETING CONTINUATION	-$754
														Subtotal = -$754

Issue Date FY: 2023 ( Subtotal = $340,811 )
2023	2023	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	4	2/22/2023	NON-COMPETING CONTINUATION	$340,811
														Subtotal = $340,811

Issue Date FY: 2022 ( Subtotal = $340,811 )
2022	2022	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	3	2/21/2022	NON-COMPETING CONTINUATION	$306,728
2022	2022	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	3	6/27/2022	NON-COMPETING CONTINUATION	$34,083
														Subtotal = $340,811

Issue Date FY: 2021 ( Subtotal = $340,811 )
2021	2021	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	2	2/18/2021	NON-COMPETING CONTINUATION	$340,811
														Subtotal = $340,811

Issue Date FY: 2020 ( Subtotal = $551,869 )
2020	2020	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	001	1	7/15/2020	SUPPLEMENT FOR EXPANSION	$224,958
2020	2020	TEXAS A&M AGRILIFE RESEARCH	2147 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Biomedical Research and Research Training	000	1	2/7/2020	NEW	$326,911
														Subtotal = $551,869

Grand Total All Awards = $1,573,548

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The role of the free energy landscape in Parkin's function and dysfunction in health and disease

Award Number: R01GM129076

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: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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