# Functional Interplay of Lipid Membrane Components: Activation, Inhibition, and Raft Formation

> **NIH NIH R35** · TEXAS TECH UNIVERSITY · 2020 · $349,929

## Abstract

We will determine how the lipid bilayer organizes around membrane proteins to regulate vital biological
functions, including signal transduction and molecular transport. Many lipids and membrane proteins associate
to form platforms called lipid rafts, which are phase-separated from the surrounding membrane. The dynamic
structure and functional importance of these intermediate-sized (5-200 nm), non-crystalline assemblies are
difficult to characterize. Many pathogenic bacteria organize lipid rafts which can increase virulence and
antibiotic resistance. In humans, rafts form to facilitate multiple signaling processes. These processes are, in
turn, involved in the pathogenesis of diseases, including Alzheimer’s, Parkinson’s, and heart disease. Atomic-
resolution dynamic structural details of these assemblies will broaden our understanding of signaling
processes and inform disease etiology. We will confront this problem using solid-state NMR (SSNMR) and
functional assays in proteoliposomes and biological membranes. Our research program is built around three
thematic thrusts: (1) To understand how the lipid environment regulates membrane proteins site-specifically.
(2) To determine how membrane proteins, in turn, order their environment. (3) To determine the degree of
long-range order and dynamic timescales of these membrane assemblies. Our first target is the KirBac1.1
prokaryotic inward-rectifier K+ (Kir) channel and an array of functional lipids, including synthetic lipids and
biological lipid extracts, known to associate with rafts. KirBac1.1 shares many behaviors with eukaryotic Kir
channels. It is activated by anionic lipids (especially cardiolipin) and has a high affinity for saturated lipids,
cholesterol, and other lipid microdomain-forming components (including hopanoids from the native organism
Burkholderia Pseudomallei). The shared regulatory and structural features between KirBac1.1 and eukaryotic
Kir channels have inspired several topics of interest: (a) How does the lipid cardiolipin maximally activate
KirBac1.1 and trigger transmembrane allostery? Cardiolipin is an essential functional lipid throughout nature,
and understanding membrane allostery will inform not only the mechanism of K+ conductance, but the means
of transmembrane communications. (b) What is the locus and mechanism of cholesterol/hopanoid induced
channel activation? Understanding this is key to determining both how sterols regulate proteins and how they
contribute to bilayer organization. (c) How do functional lipid binding sites nucleate rafts? Cardiolipin,
cholesterol, and hopanoids are all associated with modulating protein activity and membrane organization; our
aim is to understand how they create protein-lipid and lipid-lipid interactions in this process. (d) How does the
organization of the annular/nonannular lipid shell act as a secondary regulator of membrane proteins? Kir
channels are inactivated by cholesterol, but have a high affinity for rafts. How do cellula...

## Key facts

- **NIH application ID:** 9978891
- **Project number:** 5R35GM124979-04
- **Recipient organization:** TEXAS TECH UNIVERSITY
- **Principal Investigator:** Benjamin James Wylie
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,929
- **Award type:** 5
- **Project period:** 2017-08-10 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978891

## Citation

> US National Institutes of Health, RePORTER application 9978891, Functional Interplay of Lipid Membrane Components: Activation, Inhibition, and Raft Formation (5R35GM124979-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978891. Licensed CC0.

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