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Kinetic Characterisation of Disease Causing Mutations in the Embryonic and ß-Cardiac Myosin Motor Domain

Walklate, Jonathan (2016) Kinetic Characterisation of Disease Causing Mutations in the Embryonic and ß-Cardiac Myosin Motor Domain. Doctor of Philosophy (PhD) thesis, University of Kent,. (KAR id:60910)

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Abstract

Myosin myopathies are a growing area of research not only to understand the nature of the disease and how it can occur, but also to gain insight into how the myosin molecule works. Point mutations are a great way of examining how regions of myosin interact, however, given that there are over 800 amino acids in the motor domain alone, pinpointing key residues can be challenging. The missense mutations in the myosin molecule that lead to disease are ideal then to investigate residue changes that will have an effect on the function of the motor. The expression of recombinant skeletal myosin class II molecules has only recently become possible.

Another more common myopathy is hypertrophic cardiomyopathy (HCM) which can be cause by mutations in a multitude of sarcomeric proteins, most notably the ?-cardiac myosin. HCM is usually found in adolescents and young adults; however cases are beginning to emerge involving young children. Stopped-flow kinetic analysis of one of these mutations, H251N, shows more significant effects on the myosin function than 'adult' HCM mutations, including; a weaker ADP affinity, tighter ATP affinity, and slower detachment from actin rate constant. However the difference in severity is not apparently clear from the stopped-flow data alone.

These results highlight new key areas on the myosin molecule that are essential for its correct function. The myosin motor is an intricate machine with multiple parts that need further investigation to truly understand its function and the impact of disease causing mutations

Item Type: Thesis (Doctor of Philosophy (PhD))
Thesis advisor: Geeves, Michael
Uncontrolled keywords: Myosin, Kinetics, Stopped-flow, Freeman-Sheldon Syndrome, Hypertrophic Cardiomyopathy
Divisions: Divisions > Division of Natural Sciences > School of Biosciences
Depositing User: Users 1 not found.
Date Deposited: 14 Mar 2017 20:00 UTC
Last Modified: 20 May 2021 13:31 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/60910 (The current URI for this page, for reference purposes)
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