# Multicomponent mechanochemical regulation of actin filament end dynamics

> **NIH NIH R35** · EMORY UNIVERSITY · 2022 · $387,123

## Abstract

ABSTRACT
Cellular actin dynamics are essential in a number of key processes such as cell migration, wound healing, cell
division and endocytosis. Physiological actin dynamics arises from a complex interplay between protein
machineries that influence either the assembly of new actin structures or the disassembly of existing actin
structures. Over the last few decades, a plethora of proteins regulating actin dynamics in cells have been
identified and individually characterized. However, we still do not fully understand how these proteins work
together in multiprotein ecosystems and how they give rise to emergent behavior that cannot be predicted simply
by adding their known individual activities. Over the last few years, I have discovered several such
multicomponent activities. I showed that an enhancer (formin) and a blocker (capping protein) of actin growth
can simultaneously bind the same site on an actin filament, in the process initiating their own dynamic exchanges
at filament ends. I also accomplished the first direct microscopic demonstration of a long-predicted but never
observed acceleration of pointed-end depolymerization of actin filaments by cyclase-associated protein (CAP)
and cofilin. Over the next five years, our goal is to uncover how multicomponent biochemical signals and
mechanical signals get integrated at the scale of individual actin filaments. We will build on our ground-breaking
discoveries by investigating other proteins that we have identified, which either directly bind filament ends or via
other end-binding proteins. We will also investigate how mechanical forces alter biochemical interactions of actin
binding proteins with actin filaments. To do this, we will employ a unique combination of microfluidics-assisted
(mf-TIRF) and multispectral single molecule imaging that I have pioneered over the last few years. We will
combine biochemical and biophysical experiments with mathematical modelling. My vision is that a better
understanding of molecular mechanisms underlying actin dynamics will pave the way for development of new
therapies to combat human ailments like Amyotrophic Lateral Sclerosis (ALS), metastatic cancer, neurological
(e.g. Alzheimer's disease and Parkinson's diseases) and developmental disorders (e.g. limb deformities) that
are caused due to abnormalities related to actin dynamics.

## Key facts

- **NIH application ID:** 10455672
- **Project number:** 5R35GM143050-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shashank Shekhar
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,123
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455672

## Citation

> US National Institutes of Health, RePORTER application 10455672, Multicomponent mechanochemical regulation of actin filament end dynamics (5R35GM143050-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455672. Licensed CC0.

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