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.
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.
|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|
|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:|
|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|
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