# New mechanisms of SERCA regulation: Dimerization and Micropeptides

> **NIH NIH R01** · LOYOLA UNIVERSITY CHICAGO · 2020 · $571,044

## Abstract

Project Summary/Abstract
The proposed project uses a two aim strategy to explore molecular mechanisms of the regulation of ion-motive
ATPases. Specifically, we will focus on regulation of calcium transporters in skeletal and cardiac muscle. While
it is important in all cells, calcium transport plays a particularly critical role in striated muscle, as the uptake of
calcium determines the kinetics of muscle relaxation. In the heart, the calcium transport rate also indirectly
determines the strength of the cardiac contraction, since it defines the magnitude of the calcium stores and
therefore the size of calcium release.
Aim 1 of the present proposal focuses on regulation of SERCA by newly discovered species of micropeptides
that are related to phospholamban. These new regulators include DWORF, endoregulin, myoregulin, and
another-regulin. Little is known about the biophysical determinants of their functional regulation of SERCA.
We will quantify the stoichiometry and binding affinity of micropeptide regulatory complexes, the dynamics of
regulatory interactions, and the structural determinants of regulation. To quantify these key parameters, we will
use several complementary approaches including fluorescence spectroscopy/microscopy, live cell physiological
measurements, in vitro functional assays, cryoEM, and NMR. Defining the basic building blocks of
micropeptide regulatory complexes is a key step in understanding their biophysical function.
Aim 2 will investigate physical and functional coupling of SERCA pumps into dimeric transport complexes.
We will investigate the regulation of functional coupling and determine its physiological consequences. In
particular, we will test how functional coupling alters SERCA transport rate and the cooperativity of calcium-
dependent ATPase activity. The experiments described in the two Aims of this application will provide new
insight into fundamental mechanisms of regulation of ion-motive ATPases, and may improve our understanding
of the ion transport disorders associated with heart failure.
The Principal Investigator has recruited collaborating investigators to provide additional methodological
expertise. Calibrated, quantitative calcium uptake measurements will be performed in live cells in the laboratory
of Prof. Aleksey Zima, Loyola University Chicago. CryoEM of DWORF-SERCA complexes will be done in
the lab of Prof. Howard S. Young, University of Alberta. NMR of DWORF will be done in the lab of Prof.
Gianluigi Veglia, University of Minnesota. Each of the collaborators already has a history of productive
collaboration with the Principal Investigator. Now they will combine their expertise as a single team to address
how micropeptides and SERCA dimerization regulate calcium handling in striated muscle. Additional expertise
in molecular biology and animal models of heart failure will be provided by Dr. Toni Pak and Dr. Ivana Kuo,
Loyola University Chicago.

## Key facts

- **NIH application ID:** 9842006
- **Project number:** 5R01HL143816-02
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Seth L Robia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $571,044
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842006

## Citation

> US National Institutes of Health, RePORTER application 9842006, New mechanisms of SERCA regulation: Dimerization and Micropeptides (5R01HL143816-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842006. Licensed CC0.

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