# Structural Basis of “Force from Lipids” Activation in Mechanosensitive Channels

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $356,400

## Abstract

Project Summary/Abstract
 Mechanosensitive (MS) channels are oligomeric membrane proteins that function as mechano-electrical
sensory switches in a wide range physiological processes. These include touch, hearing, proprioception, turgor
control in plant cells and osmoregulation in bacteria. Among these, a fundamental class of MS channels
responds to changes in the physical properties of the lipid bilayer by undergoing major structural transitions in
response to membrane tension, thus fulfilling a major role in the response of living organisms to mechanical
stimuli. This has been referred to as the “force from lipid” principle of mechanosensitivity.
 The overall, long-term goal of this project is to understand the molecular mechanism of “force from lipid”
gating in mechanosensitive channels. Specifically, we will focus on the MscS family of MS channels found in
most prokaryotes and plants. These channels are of fundamental importance in various physiological events,
can been engineered for biomedical applications, and display fascinating intramembrane heterogeneity among
family orthologs. More importantly, the MscS family Affords us the possibility of studying the functional
behavior, high resolution structure and dynamics in the same MS system.
 Although MscL and MscS channels have been studied extensively and crystal structures have been
available in multiple conformations, there are still major mechanistic questions that remain to be solved. This is
particularly true for the molecular events underlying channel gating, in light of exciting new preliminary data at
the core of this proposal. In this respect, we plan to experimentally address several fundamental questions:
What is the physical basis of the energy transduction steps, starting with trans-bilayer tension and culminating
in protein motion? What are the structures of the key functional states in its native, bilayer-embedded form?
Where in the molecule does mechanical transduction occur? And how?
 Functional studies will be designed to understand the physical basis of energy transduction. Information
on the architecture, dynamics and energetic relationship of MscS (plus other related members of the
superfamily) with its surrounding lipid bilayer will be obtained from cryo-EM, EPR analysis of spin labeled
mutants and computational methods. The data will be interpreted to generate high resolution structures of the
different stages of the gating pathway in each type of channel. We suggest that the advent of new cryo-EM
approaches to the analysis of structure and dynamics in membrane proteins in their native environment shall
open an exciting new experimental avenue that will contribute to the understanding of biologically important
events such as ion channel gating, nociception and signal transduction.

## Key facts

- **NIH application ID:** 10216309
- **Project number:** 5R01GM133191-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Eduardo A Perozo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,400
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216309

## Citation

> US National Institutes of Health, RePORTER application 10216309, Structural Basis of “Force from Lipids” Activation in Mechanosensitive Channels (5R01GM133191-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216309. Licensed CC0.

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