Post-translational regulation of cardiac myosin binding protein-C: A graphical review

Abstract

Cardiac myosin binding protein-C (cMyBP-C) is a fundamental component of the cardiac sarcomere involved in regulating systolic and diastolic activity, processes which must be tightly maintained to preserve cardiac function. Importantly, as a non-enzymatic protein, cMyBP-C relies solely on post-translational modifications and protein-protein interactions in order to modulate its function, and does so through phosphorylation, glutathionylation and acetylation amongst others. Although some are better understood than others, these modifications may represent novel therapeutic routes to modulate cMyBP-C function in the treatment of cardiac disease.

Cardiac myosin binding protein-C palmitoylation is associated with increased myofilament affinity, reduced myofilament Ca2+ sensitivity and is increased in ischaemic heart failure

“…Importantly, whilst cMyBP-C can be viewed as a negative regulator of contractility, it is heavily influenced by an increasingly developing profile of post-translational modifications that modulate its function (Main, Fuller and Baillie, 2020). In particular, at least 3 key phosphorylation sites are found in the M-domain (Ser273, Ser282 and Ser302) and cMyBP-C is highly phosphorylated in healthy myocardium (Sadayappan et al, 2005(Sadayappan et al, , 2006; Barefield and Sadayappan, 2010;Kumar et al, 2020).…”

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

“…Apart from phosphorylation, cMyBP‐C is target of other PTMs, such as redox modifications (carbonylation, S‐nitrosylation and S‐glutathionylation), acetylation and citrullination [311]. Although different effects have been proposed for these PTMs, such as protein degradation, modulation of protein‐protein interactions and regulation of sarcomere contractility and calcium sensitivity, the role of these modifications in cardiac pathophysiology remains poorly understood.…”

“…Phosphorylation of cMyBP-C has attracted a lot of attention in the last years, since it has a profound effect on cardiac contractility mainly through modulation of cMyBP-C interactions with other sarcomere partners [311,312]. Indeed, together with phosphorylation of cTnI and phospholamban, cMyBP-C phosphorylation contributes to the positive inotropy and enhanced systolic function resulting from cardiac adrenergic stimulation [313,314].…”

Identification of Phosphorylation and Other Post-Translational Modifications in the Central C4C5 Domains of Murine Cardiac Myosin Binding Protein C

“… 2 It regulates cardiac contractility in response to inotropic stimuli through phosphorylation and other post-translational modifications (PTMs). 2 − 8 The phosphorylation of the M-domain of cMyBPC via cAMP-dependent protein kinase (PKA) has been the most extensively studied PTM and has shown importance in normal cardiac function 9 by relieving the constraints on myosin S2 and accelerating cross bridge cycling. 4 , 9 − 16 In particular, phosphorylation at serine (S) residues S273, S282, and S302 (mouse residue numbering, e.g.…”

“…Cardiac myosin binding protein C (cMyBPC) is a critical regulatory protein in cardiac muscle. , It consists of 8 immunoglobulin domains and 3 fibronectin type III domains, connected by linker residues . It regulates cardiac contractility in response to inotropic stimuli through phosphorylation and other post-translational modifications (PTMs). − The phosphorylation of the M-domain of cMyBPC via cAMP-dependent protein kinase (PKA) has been the most extensively studied PTM and has shown importance in normal cardiac function by relieving the constraints on myosin S2 and accelerating cross bridge cycling. ,− In particular, phosphorylation at serine (S) residues S273, S282, and S302 (mouse residue numbering, e.g. UniProtKB O70468, unless indicated otherwise) has been implicated in many important regulatory functions in the heart. ,,,, Recent reports also indicate that PKA-mediated S307 phosphorylation in vitro may contribute to the normal physiological function and regulation of murine cMyBPC .…”