Graduate Thesis Or Dissertation


Fast kinetics of human myosin heavy chain contraction in health and disease Public Deposited

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  • The myosin heavy chain composition of human heart and skeletal muscles is dynamic in health and disease and is known to define the maximum velocity and force generated by contracting muscles. The study of the individual isoforms that comprise this diversity has recently been aided by the development of a recombinant expression system capable of producing functional sarcomeric human myosin motors. The eight primary human sarcomeric myosin isoforms are herein shown to differ by between 1.5- and 4.5-fold in their F-actin-activated ATPase activities. Due to the greatly differing contractile environments in which they function it has been anticipated that the kinetics of the reactions that comprise the contractile cycle vary to an even greater extent. Using pre-steady-state techniques it is possible to determine the kinetics of the steps of myosin contraction. Among the eight isoforms tested, we observe multiple biochemical patterns that differentiate the motors into fast-moving and slow, tension-maintaining categories. Additionally, we have characterized pathological point mutations associated with developmental and cardiac disease. We find that unique patterns of alteration to the reactions of the myosin ATPase cycle characterize each mutation. These alterations are predicted to cause significant disruptions to the reactions governing attachment and detachment between myosin and F-actin. These studies lay the foundation for structure vs. function analysis of pathological myosin mutations and fill an important void in understanding the contributions of the various myosin isoforms to human muscle contraction.
Date Issued
  • 2012
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  • 2019-11-16
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