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Dilated cardiomyopathy mutation in the converter domain of human cardiac myosin alters motor activity and response to omecamtiv mecarbil Molecular Biophysics
We investigated a dilated cardiomyopathy (DCM) mutation (F764L) in human β-cardiac myosin by determining its motor properties in the presence and absence of the heart failure drug omecamtive mecarbil (OM). The mutation is located in the converter domain, a key region of communication between the catalytic motor and lever arm in myosins, and is nearby but not directly in the OM-binding site. We expressed and purified human β-cardiac myosin subfragment 1 (M2β-S1) containing the F764L mutation, and compared it to WT with in vitro motility as well as steady-state and transient kinetics measurements. In the absence of OM we ...
Source: Journal of Biological Chemistry - November 14, 2019 Category: Chemistry Authors: Wanjian Tang, William C. Unrath, Rohini Desetty, Christopher M. Yengo Tags: Enzymology Source Type: research

Converter domain mutations in myosin alter structural kinetics and motor function Molecular Biophysics
Myosins are molecular motors that use a conserved ATPase cycle to generate force. We investigated two mutations in the converter domain of myosin V (R712G and F750L) to examine how altering specific structural transitions in the motor ATPase cycle can impair myosin mechanochemistry. The corresponding mutations in the human β-cardiac myosin gene are associated with hypertrophic and dilated cardiomyopathy, respectively. Despite similar steady-state actin-activated ATPase and unloaded in vitro motility–sliding velocities, both R712G and F750L were less able to overcome frictional loads measured in the loaded motility assay...
Source: Journal of Biological Chemistry - February 1, 2019 Category: Chemistry Authors: Laura K. Gunther, John A. Rohde, Wanjian Tang, Shane D. Walton, William C. Unrath, Darshan V. Trivedi, Joseph M. Muretta, David D. Thomas, Christopher M. Yengo Tags: Enzymology Source Type: research