Journal
JOURNAL OF STRUCTURAL BIOLOGY
Volume 192, Issue 3, Pages 331-335Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2015.09.008
Keywords
Muscle disease; Actin; Myosin; Small-angle X-ray scattering
Funding
- Medical Research Council UK
- Foundation Building Strength for Nemaline Myopathy
- Australian National Health and Medical Research Council (NHMRC) [APP1026933]
- University of Western Australia
- Australian National Health and Medical Research Council [APP1035955]
- Australian Research Council [FT100100734]
- Australian Research Council [FT100100734] Funding Source: Australian Research Council
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In humans, mutant skeletal muscle alpha-actin proteins are associated with contractile dysfunction, skeletal muscle weakness and a wide range of primarily skeletal muscle diseases. Despite this knowledge, the exact molecular mechanisms triggering the contractile dysfunction remain unknown. Here, we aimed to unravel these. Hence, we used a transgenic mouse model expressing a well-described D286G mutant skeletal muscle alpha-actin protein and recapitulating the human condition of contractile deregulation and severe skeletal muscle weakness. We then recorded and analyzed the small-angle X-ray diffraction patterns of isolated membrane-permeabilized myofibers. Results showed that upon addition of Ca2+, the intensity changes of the second (1119 nm(-1)) and sixth (1/5.9 nm(-1)) actin layer lines and of the first myosin meridional reflection (1/14.3 nm(-1)) were disrupted when the thin-thick filament overlap was optimal (sarcomere length of 2.5-2.6 mu m). However these reflections were normal when the thin and thick filaments were not interacting (sarcomere length > 3.6 mu m). These findings demonstrate, for the first time, that the replacement of just one amino acid in the skeletal muscle alpha-actin protein partly prevents actin conformational changes during activation, disrupting the strong binding of myosin molecules. This leads to a limited myosin-related tropomyosin movement over the thin filaments, further affecting the amount of cross-bridges, explaining the contractile dysfunction. (C) 2015 Elsevier Inc. All rights reserved.
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