A myopathy-linked tropomyosin mutation severely alters thin filament conformational changes during activation
2010 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 21, 9807-9812 p.Article in journal (Refereed) Published
Human point mutations in alpha- and beta-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.
Place, publisher, year, edition, pages
2010. Vol. 107, no 21, 9807-9812 p.
actin, cross-bridge, single-muscle fiber, X-ray diffraction
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-136199DOI: 10.1073/pnas.1001733107ISI: 000278054700060PubMedID: 20457903OAI: oai:DiVA.org:uu-136199DiVA: diva2:376445