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

Main, A.; Milburn, G. N.; Balesar, R. M.; Rankin, A. C.; Smith, G. L.; Campbell, K.; Baillie, G. S.; van der Velden, J.; Fuller, W.

doi:10.1101/2022.06.21.496992

bioRxiv · 10.1101/2022.06.21.496992

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

Main, A.·Milburn, G. N.·Balesar, R. M.·Rankin, A. C.·Smith, G. L.·Campbell, K.·Baillie, G. S.·van der Velden, J.·Fuller, W.

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Abstract

Cardiac myosin binding protein-C (cMyBP-C) is an essential regulator of cardiac contractility through its interactions with the thick and thin filament. cMyBP-C is heavily influenced by post-translational modifications, including phosphorylation which improves cardiac inotropy and lusitropy, and S-glutathionylation, which impairs phosphorylation and is increased in heart failure. Palmitoylation is an essential cysteine modification that regulates the activity of cardiac ion channels and soluble proteins, however, its relevance to myofilament proteins has not been investigated. In the present study, we purified palmitoylated proteins from ventricular cardiomyocytes and identified that cardiac actin, myosin and cMyBP-C are palmitoylated. The palmitoylated form of cMyBP-C was more resistant to salt extraction from the myofilament lattice than the non-palmitoylated form. Isometric tension measurements suggest c-MyBP-C palmitoylation reduces myofilament Ca2+ sensitivity, with no change to maximum force or passive tension. Importantly, cMyBP-C palmitoylation levels are reduced at the site of injury in a rabbit model of heart failure but increased in samples from patients with ischaemic heart failure. Identification of cMyBP-C palmitoylation site revealed S-glutathionylated cysteines C635 and C651 are required for cMyBP-C palmitoylation, suggesting an interplay between the modifications at these sites. We conclude that structural and contractile proteins within the myofilament lattice are palmitoylated, with important functional consequences for cardiac contractile performance.

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Main, A., Milburn, G. N., Balesar, R. M., Rankin, A. C., Smith, G. L., Campbell, K., Baillie, G. S., van der Velden, J., Fuller, W.. 2022-06-21. Cardiac myosin binding protein-C palmitoylation is associated with increased myofilament affinity, reduced myofilament Ca2+ sensitivity and is increased in ischaemic heart failure.. https://doi.org/10.1101/2022.06.21.496992

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