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The high Ca2+-sensitivity associated with the Glu139del and Arg91Gly mutations in tropomyosin is caused by freezing of tropomyosin near the closed positionтезисы доклада
- Авторы: Karpicheva OE, Simonyan AO, Rysev NA, Sirenko VV, Redwood CS, Borovikov YS
- Сборник: Abstracts of 46th European Muscle Conference
- Тезисы
- Год издания: 2017
- Место издания: Potsdam
- Первая страница: 96
- Последняя страница: 96
- Аннотация: Deletion of glutamic acid residue at position 139 (Glu139del) and substitution of arginine 91 for glycine (Arg91Gly) in β-tropomyosin are caused by point mutations in TPM2 gene. The latter are associated with cap myopathy and distal arthrogryposis, respectively, and both are characterized by high Ca2+ sensitivity of myofilaments. To understand the mechanisms of these defects we studied multistep changes in mobility and spatial arrangement of tropomyosin, actin and myosin heads during the ATPase cycle in reconstituted ghost fibers using the fluorescent probes associated with respective proteins and polarized fluorescence microscopy. The Glu139del and Arg91Gly mutations was shown to increase strongly the flexibility of tropomyosin and freeze the tropomyosin strands near the closed position. Both mutations inhibited the movement of the tropomyosin strands towards the blocked position at low Ca2+, thus causing higher Ca2+ sensitivity. The Glu139del mutation decreased while the Arg91Gly mutation increased the amount of the myosin heads strongly bound to F-actin at high Ca2+, but both increased the number of such heads at relaxation; this may contribute to contractures and muscle weakness. The relative number of actin monomers in the «OFF» state at low Ca2+ was increased in the presence of both tropomyosins. Therefore, the ability of troponin to switch actin monomers off at low Ca2+ was retained. It was suggested that the high Ca2+ sensitivity in the presence of these mutations is not associated with a failure in troponin action, but rather arises from the abnormal position of the mutant tropomyosins on the actin filaments and hence an increase in the population of the strongly bound myosin heads at low Ca2+. The use of reagents that decrease the Ca2+ sensitivity of the troponin complex may not be appropriate to restore muscle function in patients with the Glu139del and Arg91Gly mutations. This work was supported by the Russian Science Foundation (grant 17-14-01224).
- Добавил в систему: Карпичева Ольга Евгеньевна