# Structural Mechanisms of Cytoskeletal Force-Sensing

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2022 · $339,000

## Abstract

PROJECT SUMMARY
 Cells in the body perceive cues from their local environment, which control cellular behavior through a
coordinated series of molecular events known as signaling. Signaling is critically important for telling a cell if it
should grow and divide, migrate to a different part of the body, or commit suicide if it has completed its function
or been irreparably damaged. Frequently, signaling processes are found to be working incorrectly in diseased
cells. For instance, cancer cells divide and migrate out of control and ignore cues which should keep them in
check. Signals come in multiple forms. Specific molecules bind and activate cognate receptor proteins in the cell,
known as “chemical signaling”, which is broadly well-understood. Physical forces and the rigidity of a cell’s
environment also elicit specific cell behaviors, but we have a comparatively poor understanding of how proteins
transmit these “mechanical signals”. A significant fraction of successful drugs target protein molecules which
operate in chemical signaling. The development of many such treatments was stimulated by determining the
detailed three-dimensional chemical structures of the interactions between receptor proteins and the molecules
which activate them, facilitating the design of drugs which precisely intervene in these processes. Despite its
importance, efforts to therapeutically target mechanical signaling have been limited. The long-term goal of this
research project is to visualize how forces modulate the three-dimensional structure of mechanical signaling
proteins to activate them, in order to facilitate the development of drugs that block these changes.
 This proposal is specifically focused on understanding how cellular polymers (“filaments”) composed of
the protein actin coordinate mechanical signaling. The cell contains many networks composed of actin filaments,
myosin molecular motor proteins, and hundreds of other binding partners, which collectively generate and
transmit diverse forces. We hypothesize that specific types of forces cause distinct physical rearrangements in
actin filaments, which can be detected by other proteins in the cell through direct binding interactions. We will
identify proteins which bind actin in a force-sensitive manner (Aim 1), focusing specifically on delineating the
precise regions of the proteins which confer force-sensitivity. We will next visualize how side-wise bending forces
(Aim 2) and length-wise tensile and compressive forces generated by myosin motor proteins (Aim 3) impact actin
filament structure, hypothesizing these force regimes produce distinct rearrangements which can be
discriminated by binding partners. In pursuit of these Aims, we are developing sample preparation and
computational image analysis approaches to visualize the three-dimensional structure of actin polymers in the
presence of mechanical forces with cryo-electron microscopy (cryo-EM). In addition to providing basic insights
into how forces ar...

## Key facts

- **NIH application ID:** 10382368
- **Project number:** 5R01GM141044-02
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** GREGORY M ALUSHIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $339,000
- **Award type:** 5
- **Project period:** 2021-04-06 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10382368

## Citation

> US National Institutes of Health, RePORTER application 10382368, Structural Mechanisms of Cytoskeletal Force-Sensing (5R01GM141044-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10382368. Licensed CC0.

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