PT - JOURNAL ARTICLE AU - Previs, Michael J. AU - Prosser, Benjamin L. AU - Mun, Ji Young AU - Previs, Samantha Beck AU - Gulick, James AU - Lee, Kyounghwan AU - Robbins, Jeffrey AU - Craig, Roger AU - Lederer, W. J. AU - Warshaw, David M. TI - Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling AID - 10.1126/sciadv.1400205 DP - 2015 Feb 01 TA - Science Advances PG - e1400205 VI - 1 IP - 1 4099 - http://advances.sciencemag.org/content/1/1/e1400205.short 4100 - http://advances.sciencemag.org/content/1/1/e1400205.full SO - Sci Adv2015 Feb 01; 1 AB - The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by exquisitely sensitizing the contractile apparatus to calcium in a manner that precisely counterbalances the calcium gradient. Thus, the presence and correct localization of MyBP-C within the sarcomere is critically important for normal cardiac function, and any disturbance of MyBP-C localization or function will contribute to the consequent cardiac pathologies.