# Post translational modifications tune cardiac myosin

> **NIH NIH R15** · UNIVERSITY OF NORTH CAROLINA CHARLOTTE · 2021 · $440,010

## Abstract

ABSTRACT
We hypothesize that the post-translational modification (PTM) of the heavy chain of human
cardiac myosin head (S1) regulates myosin allosteric transition between two distinct states,
active, ready to interact with actin and the sequestered super-relaxed state when myosin S1
bound to the proximal S2 domain of myosin tail and sterically constrained from the interaction
with actin. Rapid and reversible switch between myosin structural states could be a regulatory
mechanism of muscle activation when more active heads become available in a sarcomere for
force production. The proposal is based on (a) our recent success in the expression and
purification of human cardiac myosin using the C2C12 murine myoblasts expression system, and
(b) on the successful application of a toolset of complementary biophysical methods to study
myosin and actomyosin kinetics, myosin motility, and myosin S1-S2 interactions. We propose to
study three selected PTM-mimetic mutants of the human cardiac myosin. We will examine the
effect of mutations on the kinetics of the actomyosin cycle, the binding affinity of myosin S1 and
proximal S2, the population of myosin in the sequestered SRX state, and unloaded and loaded
in vitro motility of the PTM-mimetic myosin constructs. Two aims of the proposal are
complementary. The changed kinetics of the actomyosin cycle will be detected in the transient
kinetics experiments and as the changed velocity of actin filament in the unloaded in vitro
motility assay. The affected stability of the SRX state will be assessed directly in the single
turnover ATP assay and will be detected as changed ensemble force of myosin bed in the
loaded in vitro motility assay. As the result, we will examine our hypothesis that PTM
destabilizes the SRX state of myosin and will characterize the effect of PTM on human cardiac
myosin kinetics and motility.

## Key facts

- **NIH application ID:** 10291447
- **Project number:** 1R15HL159585-01
- **Recipient organization:** UNIVERSITY OF NORTH CAROLINA CHARLOTTE
- **Principal Investigator:** YURI NESMELOV
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,010
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-11-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291447

## Citation

> US National Institutes of Health, RePORTER application 10291447, Post translational modifications tune cardiac myosin (1R15HL159585-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10291447. Licensed CC0.

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