# Regulation of the actin filament pointed end dynamics in health and disease

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2020 · $379,354

## Abstract

Alterations in the thin filaments involved in cardiac/skeletal muscle contraction often produce
cardiomyopathies/nemaline myopathies with fatal consequences. Our long-term goal is to identify the
components and molecular mechanisms regulating actin architecture in muscle during normal development
and disease. Our short-term goal is to determine the mechanisms of how thin filament lengths are regulated by
the actin filament pointed end binding proteins, leiomodin (Lmod) and tropomoduin (Tmod). Polymerization at
the pointed end determines thin filament length and is regulated directly by the binding of tropomodulin (Tmod)
and leiomodin (Lmod). This binding is enhanced by the integral thin filament component, tropomyosin (Tpm).
We hypothesize that maintenance of thin filament length requires the antagonistic action of Tmod and Lmod;
that is, the role of Tmod is to prevent elongation at the pointed end while Lmod allows elongation. We also
predict that Tmod and Lmod binding and action at the pointed end is determined by different arrangements of
their Tpm- and actin-binding sites. To achieve our goals, a powerful, multidisciplinary collaboration has been
established between the Kostyukova laboratory at Washington State University (with expertise in protein
structure, structural biochemistry and biophysical properties of actin filaments and regulatory proteins) and the
Gregorio laboratory at the University of Arizona (with expertise in the molecular, cellular and developmental
biology of myofibril assembly). In this proposal we will combine a broad range of state-of-the-art approaches
such as determination of high-resolution atomic structure of Lmod /Tpm binding interface, and use of advanced
microscopy and physiological assessment of myocytes from Lmod2 or Lmod3 null mice to test our molecular
designs. The proposed experiments will connect Lmod-related thin filament alterations with familial
myopathies. A better understanding of thin filament function and of its regulation is critical to better understand
muscle disease pathogenesis, to improve diagnostics and to potentially identify novel drug targets.

## Key facts

- **NIH application ID:** 9936167
- **Project number:** 5R01GM120137-04
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Carol C Gregorio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,354
- **Award type:** 5
- **Project period:** 2017-06-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936167

## Citation

> US National Institutes of Health, RePORTER application 9936167, Regulation of the actin filament pointed end dynamics in health and disease (5R01GM120137-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9936167. Licensed CC0.

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