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The effect of the skeletal myopathy-causing E117K mutation in human β-tropomyosin on actomyosin structure during the ATPase cycle was studied using fluorescent probes bound to actin subdomain 1 and the myosin head. Multistep changes in flexural rigidity of actin filament and in spatial arrangement of actin subdomain 1 and myosin SH1 helix in troponin-free ghost muscle fibers were revealed. During the ATPase cycle E117K tropomyosin inhibited the rotation of subdomain 1 by 46% and the tilt of the SH1 helix by 49% compared with wild-type. At strong-binding stages the proportion of strong binding sub-states in the actomyosin population is decreased by the mutation. At weak-binding stages abnormally high numbers of switched-on actin monomers were observed, thus indicating a disturbance in concerted conformational changes of actomyosin. These structural alterations are likely to underlie the contractile deficit observed with this mutation.

Original publication

DOI

10.1016/j.abb.2014.03.007

Type

Journal article

Journal

Arch Biochem Biophys

Publication Date

01/05/2014

Volume

549

Pages

12 - 16

Keywords

ATPase cycle, Conformational change, Congenital myopathy, β-Tropomyosin, Actins, Actomyosin, Adenosine Triphosphatases, Animals, Humans, Muscle Fibers, Skeletal, Mutation, Protein Conformation, Rabbits, Tropomyosin