A sarcomeric protein tongue-twister: post-translation, citrullination/deimination and elimination of arginine residues

This editorial refers to ‘Citrullination of myofilament proteins in heart failure’ by J. Fert-Bober et al. , doi:10.1093/cvr/cvv185. There is now appreciation in the research community that post-translational modification (PTM) at the level of cardiac sarcomeres is a significant element in the control of cardiac contractility down-stream of Ca-signaling.1,2 These modifications are critical in the tuning of the heart beat to impositions of altered heart rate, pre-load, afterload, and metabolic demands. The constellation of cardiac sarcomeric PTMs that occur are related to the maintenance of a homeostatic state, and as with other regulatory mechanisms, when the PTMs do not synchronize with demands on cardiac function a progressive disorder may occur. With the emergence of remarkably sophisticated aches employing mass spectrometry,3,4 there has been a deeper understanding of the diversity and potential significance of PTMs of sarcomeric proteins beyond their well-characterized state of phosphorylation and oxidation. The list includes a multitude of potential modifications, and a newly discovered modification has been reported by Fert-Bober et al. 5 This novel finding indicates that a number of critical cardiac sarcomeric proteins from control human hearts and from hearts with ischaemic disease and dilated cardiomyopathy undergo deimination or citrullination in which an Arg residue is replaced with a citrulline, resulting in an irreversible loss of a negative charge and an increase in hydrophobicity. As recently reviewed by Fert-Bober and Sokolove,6 this reaction is under the control of peptidylarginine deiminase (PAD), a Ca2+-regulated enzyme with poorly understood substrate specificity. There are a number of isoforms of PAD, several of which are expressed in myocardium. However, Fert-Bober et al. 5 report that the PAD2 is …