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Unravelling Membrane Protein-Lipid Interactions using Nanodiscs and Mass Spectrometry

Award Number: R35GM128624
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: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Unravelling Membrane Protein-Lipid Interactions using Nanodiscs and Mass Spectrometry - PROJECT SUMMARY/ABSTRACT Membrane proteins are involved in many cellular processes and thus are critical drug targets for a wide range of diseases. However, there is a fundamental gap in understanding how the global changes to the lipid environment affect local membrane protein structure and function. Mounting evidence indicates that lipids can be essential for membrane protein function, but it is difficult to determine the molecular mechanisms underlying protein-lipid interactions. The primary challenge is that conventional structural biology tools and binding assays are poorly suited to characterizing transient and heterogeneous protein-lipid interactions. To advance our understanding of biological process and lay a foundation for advancing disease treatment, our goal is to develop new approaches to determine how lipid bilayers regulate membrane proteins. Studying a diverse set of membrane protein targets ranging from bacterial complexes to viral ion channels to human transporters, we are focused on answering several key questions. First, which lipids bind a given membrane protein target? Lipids are often observed in membrane protein structures, but it can be challenging to determine the identity of the lipids present in the local lipidome surrounding membrane proteins. We will use novel lipidomic lipid exchange-mass spectrometry methods to study enrichment of specific lipid species in nanodisc lipoprotein particles containing the membrane protein target. Our goal is to identify unknown lipids that bind the membrane protein targets in complex mixtures of natural lipids. Second, how and were do lipids interact with the protein? We know that lipids can be critical for membrane protein function, but it is often unclear where and how specifically they bind. We will develop new native mass spectrometry methods to determine the sites and selectivity of lipid binding to membrane protein targets. Our goal is to uncover the molecular mechanisms driving lipid specificity at specific binding sites. Finally, why are lipids important for membrane protein function? We know that bunk cellular lipids are modulated in response to disease, age, and the environment, but it is unclear how these global lipid changes affect local membrane protein physiology. We will study the function of membrane protein targets in different lipid environments and with different mutants that affect lipid binding. For lipid sites that significantly affect function, we will perform structural analysis to connect lipid binding at specific sites with functional outcomes. Our overarching goal is to understand how global lipidomic changes affect local membrane protein structure and function. This will impact biomedical research by identifying lipids important for maintaining protein activity and aiding in elucidating the physiological mechanisms of membrane proteins inside natural bilayers. Ultimately, an improved understanding of protein-lipid interactions holds the potential for improved drug discovery and for new therapeutic strategies for modulating membrane protein activity by modulating cellular lipids.


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 = $0 )
2026	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	000	8	1/14/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $425,423 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Biomedical Research and Research Training	002	8	9/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$425,423
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	001	7	9/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $425,423

Issue Date FY: 2024 ( Subtotal = $407,040 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	000	7	8/26/2024	NON-COMPETING CONTINUATION	$407,040
2024	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	002	6	9/23/2024	COMPETING CONTINUATION	$26,265
2024	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	001	5	9/23/2024	NON-COMPETING CONTINUATION	-$26,265
														Subtotal = $407,040

Issue Date FY: 2023 ( Subtotal = $407,040 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Biomedical Research and Research Training	000	6	6/19/2023	COMPETING CONTINUATION	$407,040
														Subtotal = $407,040

Issue Date FY: 2022 ( Subtotal = $365,208 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	5	9/2/2022	NON-COMPETING CONTINUATION	$365,208
														Subtotal = $365,208

Issue Date FY: 2021 ( Subtotal = $408,652 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	4	8/26/2021	NON-COMPETING CONTINUATION	$365,208
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	001	4	9/13/2021	SUPPLEMENT FOR EXPANSION	$43,444
														Subtotal = $408,652

Issue Date FY: 2020 ( Subtotal = $365,208 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	3	9/18/2020	NON-COMPETING CONTINUATION	$365,208
														Subtotal = $365,208

Issue Date FY: 2019 ( Subtotal = $444,885 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	001	2	9/3/2019	SUPPLEMENT FOR EXPANSION	$79,677
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	2	8/29/2019	NON-COMPETING CONTINUATION	$365,208
														Subtotal = $444,885

Issue Date FY: 2018 ( Subtotal = $365,208 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Biomedical Research and Research Training	000	1	8/29/2018	NEW	$365,208
														Subtotal = $365,208

Grand Total All Awards = $3,188,664

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Unravelling Membrane Protein-Lipid Interactions using Nanodiscs and Mass Spectrometry

Award Number: R35GM128624

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: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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