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

摘要: We review the recent development of novel biochemical and spectroscopic methods to determine site-specific phosphorylation, expression, mutation, structural dynamics phospholamban (PLB), in relation its function (inhibition cardiac calcium pump, SERCA2a), with specific focus on physiology, pathology, therapy. In cardiomyocyte, SERCA2a actively transports Ca2+ into sarcoplasmic reticulum (SR) during relaxation (diastole) create concentration gradient that drives passive efflux required for contraction (systole). Unphosphorylated PLB (U-PLB) inhibits SERCA2a, but phosphorylation at S16 and/or T17 (producing P-PLB) changes structure relieve inhibition. Because insufficient activity is a hallmark heart failure, activation, by gene therapy (Andino et al. 2008; Fish 2013; Hoshijima 2002; Jessup 2011) or drug (Ferrandi Huang Khan 2009; Rocchetti Zhang 2012), widely sought goal treatment failure. This describes rational approaches this goal. Novel biophysical assays, using site-directed labeling high-resolution spectroscopy, have been developed resolve states SERCA2a-PLB complexes vitro living cells. synthetic standards multidimensional immunofluorescence, quantitate expression cells human tissues. The properties U-PLB, P-PLB, mutant will ultimately mechanisms loss inhibition gain guide therapeutic development. These assays be powerful tools investigating tissue samples from Sydney Heart Bank, purpose analyzing diagnosing disorders.