- "Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function"
Tong CW, Stelzer JE, Greaser ML, et al., Circ Res Sep 2008. Furthermore, cMyBP-C(t3SA) hearts exhibited basal echocardiographic findings of systolic dysfunction, diastolic dysfunction, and hypertrophy. Conversely, cMyBP-C(tWT) hearts performed similar to WT. Thus, PKA phosphorylation of cMyBP-C accelerates crossbridge kinetics and loss of this regulation leads to cardiac dysfunction.
- "Protein kinase A-mediated phosphorylation of cMyBP-C increases proximity of myosin heads to actin in resting myocardium"
Colson BA, Bekyarova T, Locher MR, et al., Circ Res 103 (3): 244-251 Aug 2008. We favor a mechanism in which cMyBP-C modulates cross-bridge cycling kinetics by regulating the proximity and interaction of myosin and actin. To test this idea, we used synchrotron low-angle x-ray diffraction to measure interthick filament lattice spacing and the equatorial intensity ratio, I(11)/I(10), in skinned trabeculae isolated from wild-type and cMyBP-C null (cMyBP-C(-/-)) mice.
- "Intramolecular interactions in the N-domain of cardiac troponin C are important determinants of calcium sensitivity of force development"
Reece KL, Moss RL, Biochemistry 47 (18): 5139-5146 May 2008. Except for the serine mutation, cysteine substitution had no effect on Ca (2+) binding on c TnC in solution. However, as part of the myofilament, the threonine mutation reduced Ca (2+) sensitivity while the phenylalanine mutation increased Ca (2+) sensitivity. Analysis of the available crystal and NMR structures reveals specific structural mechanisms for these effects.
- "Three-dimensional structure of vertebrate cardiac muscle myosin filaments"
Zoghbi ME, Woodhead JL, Moss RL, et al., Proceedings of the National Academy of Sciences of the United States of America 105 (7): 2386-2390 Feb 2008. We have used electron microscopy and image analysis to determine the three-dimensional structure of myosin filaments from wild-type mouse cardiac muscle and from a MyBP-C knockout model for HCM. These observations provide key insights into the role of the myosin filament in cardiac contraction, assembly, and disease. The techniques we have developed should be useful in studying the structural basis of other myosin-related HCM diseases.