# Diversity Supplement to Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $31,532

## Abstract

Title of project: DIVERSITY SUPPLEMENT TO STRUCTURAL DYNAMICS OF CARDIAC MYOSIN-BINDING
PROTEIN C REGULATION.
Myosin-binding protein C (MyBP-C) plays a major role in the modulation of cardiac function by its
phosphorylation and causes deficits in contractile function due to MyBP-C mutations in hypertrophic
cardiomyopathy (HCM) and reduced phosphorylation in heart failure. Our goal is to understand the molecular
biophysics of muscle, with particular emphasis on the heart, and to train the next generation of muscle
biophysicists, inclusive of diverse trainees. The parent research project and diversity supplement ask
fundamental questions about the role of protein interactions and structural dynamics that regulate function in
cardiac muscle. To gain insight into the correlation of structure-function involved in MyBP-C mechanisms in
physiological and pathological settings, we will probe the actin-myosin-MyBP-C complex of these proteins in
solution with varied binding, phosphorylation, and HCM mutations. Our core technology is site-directed
spectroscopy, applied to purified MyBP-C and actin/myosin filaments. We will apply innovative complementary
methods in site-directed labeling and spectroscopy to correlate protein binding, structural dynamics and function.
We will test the central hypothesis that phosphorylation and HCM mutations of N-terminal MyBP-C alter
functionally significant structural properties of MyBP-C alone and as it interacts with actin and myosin. Related
to parent grant Aim 1, the first period of the diversity supplement focuses on using spectroscopic approaches to
accurately measure the structural dynamics within M-domain of purified MyBP-C, where phosphorylation occurs,
primarily by measuring nanometer distances and molecular disorder. Major emphasis is placed on detection of
conformational changes (structure) within MyBP-C’s M-domain due to phosphorylation, HCM mutation, and actin
or myosin binding (function). By including the location of probes in M-domain, the Candidate will measure
structural changes predicted from our computational simulations. Fluorescently-labeled MyBP-C will be prepared
to acquire fluorescence lifetime using time-resolved methods. In the second period, the Candidate will learn new
skills in spectroscopic data fitting analysis to determine probe-to-probe distances and disorder in N-terminal
MyBP-C. The third period will contribute to both Aim 1 and Aim 2 by providing molecular details of the structural
dynamics of the actin-MyBP-C complex with added troponin, tropomyosin, and myosin to mimic physiological
conditions of the cardiac thin filament in muscle. The Candidate will systematically build in model system
complexity, from actin-bound to thin filament-bound MyBP-C, with low (diastole) or high (systole) activator Ca2+,
and upon binding of cardiac myosin, providing key insights at the myofilament level to be applied for
understanding fundamental mechanisms in the muscle cell. Spectroscopic study of MyBP-C r...

## Key facts

- **NIH application ID:** 10412720
- **Project number:** 3R01HL141564-03S1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Brett A Colson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,532
- **Award type:** 3
- **Project period:** 2021-08-31 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412720

## Citation

> US National Institutes of Health, RePORTER application 10412720, Diversity Supplement to Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation (3R01HL141564-03S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10412720. Licensed CC0.

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