The most prevalent Freeman-Sheldon Syndrome mutations in the embryonic myosin motor share functional defects

Walklate, J., Vera, C., Bloemink, M. J., Geeves, M. A. and Leinwand, L. A. (2016) The most prevalent Freeman-Sheldon Syndrome mutations in the embryonic myosin motor share functional defects. The Journal of Biological Chemistry, 291. pp. 10318-10331. ISSN 0021-9258.

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The embryonic myosin isoform is expressed during fetal development and rapidly down-regulated after birth. Freeman-Sheldon syndrome (FSS) is a disease associated with missense mutations in the motor domain of this myosin. It is the most severe form of distal arthrogryposis, leading to overcontraction of the hands, feet, and orofacial muscles and other joints of the body. Availability of human embryonic muscle tissue has been a limiting factor in investigating the properties of this isoform and its mutations. Using a recombinant expression system, we have studied homogeneous samples of human motors for the WT and three of the most common FSS mutants: R672H, R672C, and T178I. Our data suggest that the WT embryonic myosin motor is similar in contractile speed to the slow type I/β cardiac based on the rate constant for ADP release and ADP affinity for actin-myosin. All three FSS mutations show dramatic changes in kinetic properties, most notably the slowing of the apparent ATP hydrolysis step (reduced 5–9-fold), leading to a longer lived detached state and a slowed Vmax of the ATPase (2–35-fold), indicating a slower cycling time. These mutations therefore seriously disrupt myosin function.

Item Type: Article
Uncontrolled Keywords: enzyme kinetics, molecular motor, recombinant protein expression, skeletal muscle, ATPase myosin subfragment 1, stopped-flow, human myosin, transient kinetics, motor domain, muscle disease
Subjects: Q Science > QH Natural history > QH0301 Biology (General)
Q Science > QM Human anatomy > QM0601 Human embryology
Divisions: Faculty of Social and Applied Sciences > School of Human and Life Sciences
Depositing User: Marieke Bloemink
Date Deposited: 12 May 2016 15:18
Last Modified: 03 Dec 2017 09:44

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Last edited: 29/06/2016 12:23:00