# Unravelling Membrane Protein-Lipid Interactions using Nanodiscs and Mass Spectrometry

> **NIH NIH R35** · UNIVERSITY OF ARIZONA · 2024 · $407,040

## Abstract

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 i...

## Key facts

- **NIH application ID:** 10871807
- **Project number:** 5R35GM128624-07
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Michael T Marty
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $407,040
- **Award type:** 5
- **Project period:** 2018-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871807

## Citation

> US National Institutes of Health, RePORTER application 10871807, Unravelling Membrane Protein-Lipid Interactions using Nanodiscs and Mass Spectrometry (5R35GM128624-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871807. Licensed CC0.

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