Myosin transducer mutations differentially affect motor function, myofibril structure, and the performance of skeletal and cardiac muscles.
Striated muscle myosin is a multidomain ATP-dependent molecular motor. Alterations to various domains affect the chemomechanical properties of the motor, and they are associated with skeletal and cardiac myopathies. The myosin transducer domain is located near the nucleotide-binding site. Here, we helped define the role of the transducer by using an integrative approach to study how Drosophila melanogaster transducer mutations D45 and Mhc(5) affect myosin function and skeletal and cardiac muscle structure and performance. We found D45 (A261T) myosin has depressed ATPase activity and in vitro actin motility, whereas Mhc(5) (G200D) myosin has these properties enhanced. Depressed D45 myosin activity protects against age-associated dysfunction in metabolically demanding skeletal muscles. In contrast, enhanced Mhc(5) myosin function allows normal skeletal myofibril assembly, but it induces degradation of the myofibrillar apparatus, probably as a result of contractile disinhibition. Analysis of beating hearts demonstrates depressed motor function evokes a dilatory response, similar to that seen with vertebrate dilated cardiomyopathy myosin mutations, and it disrupts contractile rhythmicity. Enhanced myosin performance generates a phenotype apparently analogous to that of human restrictive cardiomyopathy, possibly indicating myosin-based origins for the disease. The D45 and Mhc(5) mutations illustrate the transducer's role in influencing the chemomechanical properties of myosin and produce unique pathologies in distinct muscles. Our data suggest Drosophila is a valuable system for identifying and modeling mutations analogous to those associated with specific human muscle disorders.
Department of Biology and Heart Institute, San Diego State University, San Diego, CA 92182-4614, USA.
Anthony
A
Cammarato
Corey M
CM
Dambacher
Aileen F
AF
Knowles
William A
WA
Kronert
Rolf
R
Bodmer
Karen
K
Ocorr
Sanford I
SI
Bernstein
D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D001696:Biomechanical Phenomena; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D017344:Genes, Insect; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D009210:Myofibrils / Q000737:chemistry* / Q000648:ultrastructure; D009218:Myosins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D050505:Mutant Proteins; D020033:Protein Isoforms; D009218:Myosins