Phospholamban phosphorylation, mutation, and structural dynamics: a biophysical approach to understanding and treating cardiomyopathy

Biophysics Reviews
Naa-Adjeley Ablorh, David D Thomas

Abstract

We review the recent development of novel biochemical and spectroscopic methods to determine the site-specific phosphorylation, expression, mutation, and structural dynamics of phospholamban (PLB), in relation to its function (inhibition of the cardiac calcium pump, SERCA2a), with specific focus on cardiac physiology, pathology, and therapy. In the cardiomyocyte, SERCA2a actively transports Ca2+ into the sarcoplasmic reticulum (SR) during relaxation (diastole) to create the concentration gradient that drives the passive efflux of Ca2+ required for cardiac contraction (systole). Unphosphorylated PLB (U-PLB) inhibits SERCA2a, but phosphorylation at S16 and/or T17 (producing P-PLB) changes the structure of PLB to relieve SERCA2a inhibition. Because insufficient SERCA2a activity is a hallmark of heart failure, SERCA2a activation, by gene therapy (Andino et al. 2008; Fish et al. 2013; Hoshijima et al. 2002; Jessup et al. 2011) or drug therapy (Ferrandi et al. 2013; Huang 2013; Khan et al. 2009; Rocchetti et al. 2008; Zhang et al. 2012), is a widely sought goal for treatment of heart failure. This review describes rational approaches to this goal. Novel biophysical assays, using site-directed labeling and high-resolution spectroscopy...Continue Reading

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Citations

Dec 10, 2015·Expert Review of Cardiovascular Therapy·Paul F KantorSteven E Lipshultz
May 16, 2018·Diabetes & Vascular Disease Research : Official Journal of the International Society of Diabetes and Vascular Disease·Gang LiuXiao Yong Tong
Jun 14, 2020·International Journal of Molecular Sciences·Rodrigo Aguayo-Ortiz, L Michel Espinoza-Fonseca
Oct 30, 2020·Nucleic Acids Research·Georgina CsizmadiaTamás Hegedűs

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