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Center: LipiX-MS: Chemical Crosslinking Mass Spectrometry Approach for Decoding Lipid-Protein Interactions

Award Number: R35GM143047
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: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Center: LipiX-MS: Chemical Crosslinking Mass Spectrometry Approach for Decoding Lipid-Protein Interactions - PROJECT SUMMARY/ABSTRACT Lipids are essential biomolecules involved in membrane structure, signaling, and energy storage. Their interactions with proteins regulate critical cellular functions, yet lipid–protein interactions remain poorly characterized due to their dynamic nature and the structural complexity of lipids. Current analytical methods, such as crystallography, cryo-EM, and biochemical assays, each offer valuable but limited insights, underscoring the need for complementary approaches to fully unravel the complexity of lipid–protein interactions. We propose LipiX-MS, a novel crosslinking mass spectrometry (MS) platform designed specifically to decode lipid–protein interactions with high structural precision. LipiX-MS leverages rationally designed lipid–protein crosslinkers (LPXs) that target common lipid features, such as carbon–carbon double bonds, using our previously established N–H aziridination chemistry. These LPXs covalently link lipids to nearby protein residues, incorporating MS- cleavable linkers and enrichment handles to enable sensitive and confident identification of crosslinked peptides. The platform will enable site-specific mapping of lipid–protein interactions, reveal protein conformational changes upon lipid binding, and provide insights into the structural basis of lipid selectivity and function. We present proof- of-concept data using aziridinated oleic acid and the lipid-binding protein β-lactoglobulin, demonstrating successful crosslinking, peptide-level localization, and structural insights beyond conventional methods. We will expand this approach in the first thrust by developing a diverse LPX library with tunable spacer lengths and reactivity, optimizing workflows for model and biologically relevant lipid–protein systems, and integrating native MS and HDX-MS to assess structural dynamics. A second thrust will incorporate lipid isomer resolution into the LipiX-MS workflow. Using aziridination and metal–lipid complexation strategies, we will distinguish lipid isomers at the level of double bond position, geometry, and sn-position, enabling detailed analysis of isomer-dependent protein interactions. The third thrust introduces quantitative capabilities through isobaric LPXs (i-LPXs), enabling multiplexed comparison of lipid–protein interaction profiles across biological conditions. We will apply this to investigate lipid binding and conformational regulation in Sec14, a lipid transfer protein implicated in signaling and targeted drug development. LipiX-MS represents a transformative advance in structural lipidomics, overcoming long-standing technical barriers. It will establish a powerful platform for mapping and quantifying lipid–protein interactions with isomeric resolution, with broad applications in cell biology, pharmacology, and disease research. This work lays the foundation for uncovering novel therapeutic targets and advancing lipid- driven biological understanding.


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 = $414,114 )
2026	2026	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	6	7/15/2026	COMPETING CONTINUATION	$414,114
														Subtotal = $414,114

Issue Date FY: 2025 ( Subtotal = $378,750 )
2025	2025	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	5	7/29/2025	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2024 ( Subtotal = $378,750 )
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	4	8/29/2024	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2023 ( Subtotal = $628,750 )
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	001	3	8/2/2023	SUPPLEMENT FOR EXPANSION	$250,000
2023	2023	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	3	8/1/2023	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $628,750

Issue Date FY: 2022 ( Subtotal = $378,750 )
2022	2022	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	2	8/25/2022	NON-COMPETING CONTINUATION	$378,750
														Subtotal = $378,750

Issue Date FY: 2021 ( Subtotal = $378,750 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	9/1/2021	NEW	$378,750
														Subtotal = $378,750

Grand Total All Awards = $2,557,864

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Center: LipiX-MS: Chemical Crosslinking Mass Spectrometry Approach for Decoding Lipid-Protein Interactions

Award Number: R35GM143047

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: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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