# Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $638,191

## Abstract

PROJECT SUMMARY
Hypertrophic cardiomyopathy (HCM) is a disease affecting more than 1 in 500 individuals and is an unmet
medical need with limited FDA-approved treatments. ~40% of 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 and centrally positioned in the sarcomere to regulate
interactions between myosin and actin responsible for force development. We previously demonstrated that
increased phosphorylation of MyBP-C, enhances actin-myosin interactions to accelerate contraction kinetics in
myocardium, whereas the decreased MyBP-C phosphorylation, reduces actin-myosin proximity and decelerate
contraction. However, it is remains unknown how MyBP-C functions under varied states, including myofilament
activation, phosphorylation, and HCM mutations. The structural dynamics of MyBP-C and its interactions with
actin and/or myosin to modulate force development in myocardium are key to understanding this mechanism of
action. We have developed innovative biophysical tools that, for the first time, enable determination of these
mechanisms by evaluation of: (1) MyBP-C structural dynamics, (2) how it interacts with actin and myosin in
relaxed and activated muscle, (3) how these interactions are affected by phosphorylation and (4) known
pathologic mutations. We will test the central hypothesis that MyBP-C function is determined by dynamic
structural changes of its domains that determine interactions of MyBP-C with thin (actin) and thick (myosin)
filaments and that the equilibrium of these interactions is affected by phosphorylation and HCM mutations. The
proposed aims further develop our innovative biophysical tools to measure structural dynamics underlying MyBP-
C regulation of contraction in normal and diseased states. These tools include site-directed fluorescence
spectroscopy, computational simulations, thin and thick filament function, and mechanical measurements. We
will examine how the activation state of the myocardium (Aim 1), phosphorylation of MyBP-C (Aim 2), and HCM
mutations (Aim 3) affect MyBP-C’s structural dynamics and interactions to modulate cardiac contractility. The
proposed studies resolve interactions in real myocardial space and capture structural dynamics in real time using
high-resolution approaches during the contractile cycle. This involves monitoring distances between points on
proteins and the order (or disorder) of those distances under physiological conditions, in interacting proteins and
functioning myocardium. Fluorescence lifetime data components, thin and thick filament activation, mechanics,
and simulations will be used to define models of MyBP-C regulation. The proposed aims offer unprecedented
mechanistic resolution of MyBP-C for its functions in health and HCM disease. This mechanistic understanding
is critical to lay the foundation for determining the qualitative and qu...

## Key facts

- **NIH application ID:** 10883408
- **Project number:** 2R01HL141564-06A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Brett A Colson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $638,191
- **Award type:** 2
- **Project period:** 2019-01-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883408

## Citation

> US National Institutes of Health, RePORTER application 10883408, Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation (2R01HL141564-06A1). Retrieved via AI Analytics 2026-06-15 from https://api.ai-analytics.org/grant/nih/10883408. Licensed CC0.

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