# Myosin Movement in Vitro-Molecular Characterization

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $579,832

## Abstract

Abstract
Myosin molecular motors play crucial, dynamic roles in most cellular processes, including contraction,
movement, and shape change. A variety of diseases owe their origins to defects in the myosin family of
molecular motors. A prime example is inherited familial hypertrophic cardiomyopathy (HCM), which leads to
hyper-contractility of the heart. HCM results from single missense mutations in various cardiac muscle
proteins, with mutations in β-cardiac myosin accounting for about 40% of these cases. HCM is not rare,
affecting 1 out of 500 people.  Current therapeutic interventions for cardiomyopathies are limited to
symptomatic relief, in large part because the molecular underpinnings of the disease – how mutations affect
the biomechanical interaction of myosin with its sarcomeric partners, and thus sarcomeric force, velocity, and
power output – are not well understood. Since HCM results from single residue mutations in human β-cardiac
myosin, it is imperative to study the human protein rather than cardiac myosins from other species, where
there are numerous residue differences from human throughout the protein. To fully understand the system, it
was important to begin with the simplest reconstituted system to elucidate the effects of these mutations on
power output. We have made substantial progress in that regard over the last few years studying just the
myosin motor domain with its essential light chain and its interaction with pure actin filaments. Next it is
important to build on the complexity of the reconstituted system, incorporating a two-headed molecule that
contains a phosphorylatable regulatory light chain, the calcium-regulatory proteins tropomyosin-troponin as
part of the actin thin filament, and a second regulatory component, myosin binding protein-C. Thus, we will use
this more complex reconstituted system and an array of assays to determine the biochemical and
biomechanical changes in the human β-cardiac myosin motor that result from a wide variety of HCM-causing
mutations, in order to get a larger picture of the variety of mechanistic reasons for the observed clinical
changes in contractility caused by these mutations.

## Key facts

- **NIH application ID:** 9850263
- **Project number:** 5R01GM033289-36
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** James Spudich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $579,832
- **Award type:** 5
- **Project period:** 1984-04-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850263

## Citation

> US National Institutes of Health, RePORTER application 9850263, Myosin Movement in Vitro-Molecular Characterization (5R01GM033289-36). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850263. Licensed CC0.

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