Abstract

The applicant proposes a two aim strategy to explore molecular mechanisms of the regulation of ion-motive ATPases.
Aim 1 focuses on the mechanism of SERCA regulation by phospholamban.
This aim will determine how calcium relieves inhibition of SERCA by phospholamban and test the novel hypothesis that there is an undiscovered second binding site on SERCA for phospholamban. The planned experiments will also reveal how phosphorylation alters the localization of the phospholamban cytoplasmic domain on the SERCA cytoplasmic headpiece. There is still no high resolution structural information relating this regulatory mechanism; it is most important unanswered question in the field.
Aim 2 will focus on the structural changes of the SERCA pump during the transport cycle. Protein structural transitions will be quantified with advanced fluorescence methods and molecular dynamics simulations. The experiments will provide information about how the physical motions of pumps are important for their biological function.

Public Health Relevance

Relevance to Public Health: This research project is focused on a protein called SERCA, the main calcium pump in the heart. This pump is at the center of cardiac calcium handling; by increasing the activity of the pump, the strength of the heart is increased in order to improve performance during exercise. Human heart failure is associated with disordered cardiac calcium handling, so SERCA an important therapeutic target.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL092321-10A1
Application #
9472103
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tjurmina, Olga A
Project Start
2008-07-01
Project End
2022-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Loyola University Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153

  Publications

Makarewich, Catherine A; Munir, Amir Z; Schiattarella, Gabriele G et al. (2018) The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy. Elife 7:
Robia, Seth L; Young, Howard S (2018) Skin cells prefer a slower calcium pump. J Biol Chem 293:3890-3891
Raguimova, Olga N; Smolin, Nikolai; Bovo, Elisa et al. (2018) Redistribution of SERCA calcium pump conformers during intracellular calcium signaling. J Biol Chem 293:10843-10856
Zak, Taylor J; Koshman, Yevgenia E; Samarel, Allen M et al. (2017) Regulation of Focal Adhesion Kinase through a Direct Interaction with an Endogenous Inhibitor. Biochemistry 56:4722-4731
Lamichhane, Rajan; Mukherjee, Santanu; Smolin, Nikolai et al. (2017) Dynamic conformational changes in the rhesus TRIM5? dimer dictate the potency of HIV-1 restriction. Virology 500:161-168
Himes, Ryan D; Smolin, Nikolai; Kukol, Andreas et al. (2016) L30A Mutation of Phospholemman Mimics Effects of Cardiac Glycosides in Isolated Cardiomyocytes. Biochemistry 55:6196-6204
Dvornikov, Alexey V; Smolin, Nikolai; Zhang, Mengjie et al. (2016) Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres. J Biol Chem 291:21817-21828
Blackwell, Daniel J; Zak, Taylor J; Robia, Seth L (2016) Cardiac Calcium ATPase Dimerization Measured by Cross-Linking and Fluorescence Energy Transfer. Biophys J 111:1192-1202
Smolin, Nikolai; Robia, Seth L (2015) A structural mechanism for calcium transporter headpiece closure. J Phys Chem B 119:1407-15
Abrol, Neha; de Tombe, Pieter P; Robia, Seth L (2015) Acute inotropic and lusitropic effects of cardiomyopathic R9C mutation of phospholamban. J Biol Chem 290:7130-40

Showing the most recent 10 out of 25 publications