The A230Y mutation in actin subdomain 4 is sufficient to cause higher calcium activation of myosin ATPase without impairing tropomyosin binding, providing insights into the molecular mechanisms of muscle contraction.
Hypothesis-generating for thin-filament Ca2+ regulation; leaves open translation to mammalian or human cardiac function.
To probe the mechanism by which Ca(2+) activates muscle contraction through tropomyosin and troponin, we have produced mutant actins using Dictyostelium discoideum. We focused on the sequence 228-232 (QTAAS) that is located in subdomain 4 of actin, because the chimera actin in which this sequence was replaced by KAYKE showed not only poorer tropomyosin binding but also the unexpected "higher Ca(2+) activation" [Saeki, K., et al. (1996) Biochemistry 35, 14465-14472]. We found that this higher Ca(2+) activation is solely due to the A230Y mutagenesis. Because A230Y mutant actin showed normal tropomyosin binding, the higher Ca(2+) activation is not the consequence of poorer tropomyosin binding. The significance of these results is discussed in view of a three-state model [McKillop, D. F., Geeves, M. A. (1993) Biophys. J. 65, 693-701].
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Saeki et al. (2000) studied this question.
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