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The role of tropomyosin position in the molecular mechanism of the regulation of actin-myosin interaction during the ATPase cycleтезисы доклада
- Авторы: Karpicheva O.E., Rysev N.A., Avrova S.V., Simonyan A.O., Redwood C.S., Borovikov Y.S.
- Сборник: International Symposium "Biological motility: new facts and hypotheses "
- Тезисы
- Год издания: 2014
- Место издания: Pushchino
- Первая страница: 108
- Последняя страница: 110
- Аннотация: The regulation of striated muscle contraction involves cooperative interactions between actin filaments, myosin heads, tropomyosin, troponin, and calcium. The critically important factor of this regulation is calcium-dependent azimuthal movements of tropomyosin strands over the surface of the actin filament induced by the binding of either S1 or troponin I to actin. The polarized fluorescence technique allows us to characterize concordant conformational changes of actin, myosin head and tropomyosin occurring in a reconstituted ghost fiber at several simulated stages of the ATPase cycle. Each transition between the intermediate stages of the cycle is characterized by definite interdependent conformational changes of F-actin and myosin heads. The overall change is interpreted as a right-hand rotation of actin subdomain-1 relative to the thin filament axis and an oppositely directed azimuthal movement of myosin SH1 helix (or myosin head) at transition from the weak- to strong-binding states. The actomyosin conformational state at each step of the ATPase cycle is shown to be strictly correlated to a definite conformation and specific position of tropomyosin strands on the surface of the thin filament. Tropomyosin shifts towards the center of the thin filament (to the “open” position) at strong-binding and towards the periphery of the thin filament (to the “blocked” position) at weak-binding states thereby increasing the amplitude of myosin SH1 helix movement and actin subdomain-1 rotation. Troponin modulates those movements in a Ca2+-dependent manner. Mutations in tropomyosin are able to stabilize its strands in the “open” position and to increase the proportion of the strong-binding actomyosin states, as was shown for the Glu180Gly and Asp175Asn α-tropomyosin mutations, associated with hypertrophic cardiomyopathy. On the other hand, these mutations prevent the formation of the weakbinding state of the myosin head thus causing the incomplete relaxation of the actomyosin system and leading to the enhanced contractility. The mutations Glu40Lys in α-tropomyosin and Glu117Lys in β-tropomyosin, on the contrary, prevent the shifting of tropomyosin strands to the “open” position stabilizing them at the periphery of the thin filament (closer to the “blocked” position) and inhibiting tropomyosin ability to move relative to actin. This behavior of the mutant tropomyosin causes a significant inhibition of the strong-binding actomyosin states formation and of the conformational changes of actin monomers and the myosin heads. The effect of the Glu40Lys and Glu117Lys mutations may explain the muscle weakness observed in dilated cardiomyopathy (DCM) and congenital fiber type disproportion, respectively. Anomalous positioning of mutant tropomyosin close to the periphery of actin filaments may also disturb the coordination of the conformational changes of actin and the myosin head during the ATPase cycle, as was observed with DCM-causing Glu54Lys mutation in α-tropomyosin, that prevents the transition of actin to the weak-binding structural state inhibiting the conformational changes of actin, but has a little impact on the work of the myosin head. The aberrant position of the mutant tropomyosin close to the center of actin filament in the case of Gln147Pro mutation in β-tropomyosin affects the weak-binding state of actomyosin increasing the proportion of strong-binding actomyosin states in the presence of ATP. This mutation associates with cap-myopathy and probably causes enhanced contractility. Defined alterations of tropomyosin position are likely to underlie the contractile deficit or vice versa gain of muscle function, which initiates the disease remodeling. This work was supported by the Russian Foundation for Basic Research (grants No. 14-04-00454a, 14-04-31527a).
- Добавил в систему: Карпичева Ольга Евгеньевна