A myopathy-linked tropomyosin mutation severely alters thin filament conformational changes during activation
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A myopathy-linked tropomyosin mutation severely alters thin filament conformational changes during activation. / Ochala, Julien; Iwamoto, Hiroyuki; Larsson, Lars; Yagi, Naoto.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 107, Nr. 21, 25.05.2010, s. 9807-12.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A myopathy-linked tropomyosin mutation severely alters thin filament conformational changes during activation
AU - Ochala, Julien
AU - Iwamoto, Hiroyuki
AU - Larsson, Lars
AU - Yagi, Naoto
PY - 2010/5/25
Y1 - 2010/5/25
N2 - Human point mutations in beta- and gamma-tropomyosin induce contractile deregulation, skeletal muscle weakness, and congenital myopathies. The aim of the present study was to elucidate the hitherto unknown underlying molecular mechanisms. Hence, we recorded and analyzed the X-ray diffraction patterns of human membrane-permeabilized muscle cells expressing a particular beta-tropomyosin mutation (R133W) associated with a loss in cell force production, in vivo muscle weakness, and distal arthrogryposis. Upon addition of calcium, we notably observed less intensified changes, compared with controls, (i) in the second (1/19 nm(-1)), sixth (1/5.9 nm(-1)), and seventh (1/5.1 nm(-1)) actin layer lines of cells set at a sarcomere length, allowing an optimal thin-thick filament overlap; and (ii) in the second actin layer line of overstretched cells. Collectively, these results directly prove that during activation, switching of a positive to a neutral charge at position 133 in the protein partially hinders both calcium- and myosin-induced tropomyosin movement over the thin filament, blocking actin conformational changes and consequently decreasing the number of cross-bridges and subsequent force production.
AB - Human point mutations in beta- and gamma-tropomyosin induce contractile deregulation, skeletal muscle weakness, and congenital myopathies. The aim of the present study was to elucidate the hitherto unknown underlying molecular mechanisms. Hence, we recorded and analyzed the X-ray diffraction patterns of human membrane-permeabilized muscle cells expressing a particular beta-tropomyosin mutation (R133W) associated with a loss in cell force production, in vivo muscle weakness, and distal arthrogryposis. Upon addition of calcium, we notably observed less intensified changes, compared with controls, (i) in the second (1/19 nm(-1)), sixth (1/5.9 nm(-1)), and seventh (1/5.1 nm(-1)) actin layer lines of cells set at a sarcomere length, allowing an optimal thin-thick filament overlap; and (ii) in the second actin layer line of overstretched cells. Collectively, these results directly prove that during activation, switching of a positive to a neutral charge at position 133 in the protein partially hinders both calcium- and myosin-induced tropomyosin movement over the thin filament, blocking actin conformational changes and consequently decreasing the number of cross-bridges and subsequent force production.
KW - Actin Cytoskeleton/chemistry
KW - Humans
KW - Muscular Diseases/genetics
KW - Mutation
KW - Stress, Mechanical
KW - Tropomyosin/chemistry
KW - X-Ray Diffraction
U2 - 10.1073/pnas.1001733107
DO - 10.1073/pnas.1001733107
M3 - Journal article
C2 - 20457903
VL - 107
SP - 9807
EP - 9812
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 21
ER -
ID: 240788819