# Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $383,750

## Abstract

PROJECT SUMMARY
Hypertrophic cardiomyopathy (HCM) is a relatively common disease affecting more than 1 in 500 individuals
and the leading cause of sudden death in young individuals and athletes. HCM is an unmet medical need with
no FDA-approved treatments. ~40% of all HCM cases are associated with mutations in the gene encoding
cardiac myosin-binding protein C (MyBP-C). MyBP-C is a thick filament-associated protein that is critical for
normal myocardial performance; it is centrally positioned in the sarcomere to regulate interactions between
myosin cross-bridges and actin thin filaments that are responsible for force development. We have previously
demonstrated that increased phosphorylation of MyBP-C enhances actin-myosin interactions leading to
accelerated contraction kinetics in myocardium, whereas reduced phosphorylation led to reduced actin-myosin
proximity and decelerated contraction. However, it is not understood how MyBP-C phosphorylation alters the
structural dynamics of its interactions with actin and/or myosin to modulate force development in normal
myocardium or how mutations alter functions that ultimately contribute to HCM pathogenesis. We have
developed innovative biophysical tools that, for the first time, enable evaluation of: (1) the structural dynamics of
MyBP-C, (2) how it interacts with actin and/or myosin in muscle, and (3) how these interactions are affected by
phosphorylation and known pathologic mutations. We will test the central hypothesis that phosphorylation and
HCM mutations of N-terminal MyBP-C alter functionally significant structural properties of MyBP-C and
interactions with actin and myosin. Aim 1 will evaluate the effects of phosphorylation, HCM mutations, and
binding to actin or myosin on MyBP-C structural dynamics. Spectroscopic approaches will be employed to detect
conformational changes (structure) within MyBP-C due to phosphorylation, HCM mutation, and actin/myosin
binding (function). Molecular dynamics (MD) simulations will be applied as a complementary approach. Aim 2
will determine how MyBP-C phosphorylation and HCM mutants affect proximities and dynamics of key
myocardial proteins. We will utilize site-directed probe technologies in skinned (demembranated) cardiac fibers
to determine how phosphorylation/mutants affect protein structure/interactions in situ to regulate contractility.
The proposed studies capture structural dynamics in real time and resolve interactions in real myocardial space
using novel high-resolution approaches. These aims are a stepwise progression developing a new paradigm for
studying normal and mutant MyBP-C during the contractile cycle. This paradigm involves monitoring distances
between points on proteins and the order (or disorder) of those distances under physiological conditions, in
interacting proteins and functioning myocardium. Not all HCM mutants impact the same functions of MyBP-C.
Time-resolved fluorescence data components, thin/thick filament dynamics, mechanics, and...

## Key facts

- **NIH application ID:** 10320335
- **Project number:** 5R01HL141564-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Brett A Colson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320335

## Citation

> US National Institutes of Health, RePORTER application 10320335, Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation (5R01HL141564-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10320335. Licensed CC0.

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