# Structural Mechanism for Gating of Mechanosensitive Channels

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $384,922

## Abstract

ABSTRACT
Structural Mechanism for Gating of Mechanosensitive Channels
Mechanical force sensation mediated by mechanosensitive channels underlies an array of fundamental
physiological processes, including hearing, touch, proprioception, osmoregulation, and morphogenesis.
Dysfunctional force sensation is associated with numerous diseases including deafness, atherosclerosis,
chronic pain and cancer. The prokaryotic mechanosensitive channel of small conductance (MscS) protects
bacterial cells from rupture under hypoosmotic downshock. A variety of MscS-like channels, found in many
organisms including bacteria, fungi, algae, and plants, form an exceptionally diverse superfamily of channels
that are crucial for management of osmotic pressure. MscS homologs are absent in animals, and thus
targeting MscS channels in pathogenic microorganisms such as bacteria and fungi could lead to new
antimicrobial treatment strategies. Current mechanistic understanding, primarily inferred from studies of the
prototypical prokaryotic channel, E. Coli MscS, remains limited. Structural, biochemical, and biophysical
analyses of complex membrane proteins such as eukaryotic MscS channels and multi-domain prokaryotic
MscS homologs have proven challenging owing to major difficulties in producing sufficiently large quantities of
biochemically stable protein samples. We have overcome these critical barriers through recent developments
in large-scale protein production and structural and functional analyses of a variety of MscS family members
with distinct membrane topologies and domain organizations. Our recent structural and functional studies of a
eukaryotic channel MSL1 have uncovered a `flattening and expansion' gating mechanism stemming from a
non-planar transmembrane domain at the resting state, which is reminiscent of the evolutionarily and
architecturally unrelated mammalian mechanosensitive Piezo channels. These results lead to our central
hypothesis that `flattening and expansion' in the transmembrane region may be a unifying gating mechanism.
With these exciting developments, we are now able to combine structural biology and electrophysiology to
address one of the central questions in mechanobiology: how do mechanosensitive channels gate?
Specifically, we aim to reveal gating transitions of a diverse set of MscS channels with distinct membrane
topologies to further evaluate this potentially universal gating mechanism. Detailed understanding of the
mechanisms will provide critical information that will ultimately lead to development of new antimicrobial
reagents and new treatment strategies for a broad spectrum of diseases associated with altered mechanical
force sensation.

## Key facts

- **NIH application ID:** 10883750
- **Project number:** 5R01GM143440-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Peng Yuan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,922
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883750

## Citation

> US National Institutes of Health, RePORTER application 10883750, Structural Mechanism for Gating of Mechanosensitive Channels (5R01GM143440-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10883750. Licensed CC0.

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