Microscale thermophoresis suggests a new model of regulation of cardiac myosin function via interaction with cardiac myosin-binding protein C

Abstract

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

“…In this sense, fluorescence microscopy experiments support the notion that the bulk of the cMyBP‐C molecule extends radially towards the actin filament both in relaxing and activating conditions, positioning its N‐terminal region far away from the myosin heads [287,288]. Remarkably, very recent in vitro data suggest that the central region of cMyBP‐C may bind myosin heads, potentially regulating their ATPase activity [296].…”

“…An equivalent interaction has also been reported for the cMyBP‐C isoform [292–294]. The M motif has been described to bind myosin S2 [295,296], and this interaction would be sufficient for the incorporation of cMyBP‐C into the cardiac sarcomere [295]. Furthermore, phosphorylation of key residues within the M motif by protein kinase A (PKA) (see section cMyBP‐C posttranslational modifications) abolishes this interaction [296,297], which has direct implications in the regulation of cardiac dynamics.…”

“…In this line, C1 has been identified as the major myosin head‐binding domain within cMyBP‐C N terminus by in vitro binding experiments using microscale thermophoresis (MST) [296]. Using MST, the interaction between C3 and myosin S1 has been recently found in two independent reports [264,296] (Fig. 6).…”

“…In this sense, a more disordered structure of the myosin heads in isolated thick filaments from Mybpc3 KO mouse models has been observed [100,113,332,333]. Recently, a hypothetical model resulting from in vitro binding data has proposed that a constitutive interaction with cMyBP‐C central domains would guide myosin heads to and away from the thin filament, tuning crossbridge formation rate [296].…”

“…The M motif has been described to bind myosin S2 [295,296], and this interaction would be sufficient for the incorporation of cMyBP-C into the cardiac sarcomere [295]. Furthermore, phosphorylation of key residues within the M motif by protein kinase A (PKA) (see section cMyBP-C posttranslational modifications) abolishes this interaction [296,297], which has direct implications in the regulation of cardiac dynamics. The interaction with myosin S2, more specifically at the vicinity of the S1-S2 hinge, has also been detected for the N-terminal cMyBP-C C1 and C2 domains [298,299] (Fig.…”