# Dynamic Lipid and Protein Organization in Cell Membranes

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $455,548

## Abstract

Abstract
A fundamental objective in membrane biology is to understand and predict how protein sequences fold and orient
in a lipid bilayer. Most studies focus on the membrane protein (MP) and the membrane insertion machinery with
little consideration of how lipid environment affects transmembrane domain (TMD) organization. The long-term
goal of this proposal is to understand the role of lipid-protein interactions in the assembly, structure and function
of MPs. Using a combined molecular genetic and biochemical approach, we established that lipid dependent
TMD orientation is dynamic (i.e., can reversibly change) during and after MP assembly in vivo and is independent
of other cellular factors in vitro. We proposed the Charge Balance Rule, which includes an acitve role for lipid
environment, to explain the dynamic behavior of MPs. We developed a library of lipid mutants of Escherichia coli
in which lipid composition can be regulated during or temporally after MP membrane insertion. The physiological
significance of membrane lipid bilayer asymmetry is an understudied area. We now add to this library a set of E.
coli strains and proteoliposome systems in which membrane lipid bilayer asymmetry can be controlled to
determine the role of lipid bilayer asymmetry in MP dynamic organization. Using this set of lipid reagents and
native or engineered MPs, we propose three integrated Specific Aims: Aim 1, We will quantify in thermodynamic
terms and determine the mechanistic and structural principles underlying the molecular driving forces, as
proposed by the Charge Balance Rule, that govern dynamic TMD topology organization as a function of
membrane lipid composition and asymmetry. Aim 2, The role of CL in cell functions is not well understood. CL
transbilayer asymmetry across any biological membrane is unknown, and there is still no reliable method for
estimating its distribution across any membrane. E. coli lacking CL display several phenotypes under aerobic
and anaerobic conditions, which would seriously compromise growth in the wild. We will address the role of CL,
its transmembrane asymmetry and the three CL synthases in supporting critical cell functions, which will be
applicable to the understanding of the importance of CL and cls gene multiplicity in pathogenic Gram-negative
bacteria. Aim 3, An essential MP (FtsK) was identified by us associated with a late stage of cell division (a defect
in phosphatidylethanolamine-lacking cells) that is topologically responsive to changes in lipid composition and
phosphorylation of its extramembrane domains. We will address how changes in lipid composition/asymmetry
and phosphorylation/dephosphorylation cycles affect the function of FtsK as an example of a physiological
function potentially governed by the Charge Balance Rule. By focusing on interfacial protein-lipid interactions in
lipid bilayers with different lipid compositions and asymmetry, measuring electric forces acting on nascent MPs
during and after assem...

## Key facts

- **NIH application ID:** 10765720
- **Project number:** 5R01GM121493-07
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Mikhail V. Bogdanov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $455,548
- **Award type:** 5
- **Project period:** 2017-09-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765720

## Citation

> US National Institutes of Health, RePORTER application 10765720, Dynamic Lipid and Protein Organization in Cell Membranes (5R01GM121493-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10765720. Licensed CC0.

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