Abstract
Molecular defects in cardiac myofilament Ca2+- regulation due to cardiomyopathy-linked mutations can be reversed by small molecules binding to troponin
Highlights
The contractile apparatus of cardiac muscle is controlled by the sarcoplasmic Ca2+-level acting upon the Ca2+ sensor, troponin
In our studies of the uncoupling effects of mutations we demonstrated that epigallocatechin-3 gallate (EGCG), originally studied as a Ca2+ desensitizer (Tadano et al, 2010; Friedrich et al, 2016), was found to be capable of restoring the coupled relationship between Ca2+-sensitivity and TnI phosphorylation in mutant thin filaments to normal in vitro, a property we refer to as “recoupling” (Papadaki et al, 2015; Messer et al, 2016, 2017)
We measured the Ca2+ activation of contractility using an in vitro motility assay that measures the movement of reconstituted thin filaments over a bed of immobilized myosin heads
Summary
The contractile apparatus of cardiac muscle is controlled by the sarcoplasmic Ca2+-level acting upon the Ca2+ sensor, troponin. Whilst the structural mechanism of the troponin Ca2+ switch is well-documented (Takeda et al, 2003), the structural basis of lusitropy is poorly understood since both the phosphorylated N-terminal peptide and the regulatory “switch peptide” of TnI are intrinsically disordered, recent studies using molecular dynamics simulations have begun to explain this phenomenon (Papadaki and Marston, 2016) The study of this phosphorylation dependent regulation has been recently stimulated by the discovery that a primary effect of many mutations in thin filament proteins associated with cardiomyopathy is the uncoupling of this relationship (Bayliss et al, 2012; Memo et al, 2013; Messer and Marston, 2014). Consideration of the molecular structures of re-coupling molecules (structure-activity relationships, SAR), compared with similar inactive molecules can provide considerable insight into the mechanism of recoupling and may lead to the discovery of more potent recoupling (lead) compounds with therapeutic potential
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