Several cardiomyopathy causing mutations on tropomyosin either destabilize the active state of actomyosin or alter the binding properties of tropomyosin
Several cardiomyopathy causing mutations on tropomyosin either destabilize the active state of actomyosin or alter the binding properties of tropomyosin
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DOI：
10.1016/j.bbrc.2011.01.112
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发表时间：
2011-03-04
影响因子：
3.1
通讯作者：
Chalovich, Joseph M.
中科院分区：
文献类型：
--
作者：
Mathur, Mohit C.;Chase, P. Bryant;Chalovich, Joseph M.
我们检测了引起心肌病的原肌球蛋白突变E180 G。D175 N和V95 A，以确定它们对肌动球蛋白调节的作用。V95 A降低ATP酶速率时，细丝饱和的调节蛋白在存在和不存在的钙，表明无论是稳定的非活性状态或无法完全填充的活性状态。E180 G和D175 N的作用更为复杂。与野生型原肌球蛋白相比，这两种突变在肌钙蛋白和原肌球蛋白的亚饱和浓度下增加ATP酶速率。在较高浓度的调节蛋白，ATP酶速率变得类似于野生型。在饱和调节蛋白浓度下，用紧密结合的肌球蛋白类似物N-乙基马来酰亚胺-S1实现正常激活。这些结果表明E180 G和D175 N突变降低了原肌球蛋白对肌动蛋白的亲和力，也使肌钙蛋白与肌动蛋白细丝的结合不稳定。(C)2011 Elsevier Inc. All rights reserved.
We examined the cardiomyopathy-causing tropomyosin mutations E180G. D175N, and V95A to determine their effects on actomyosin regulation. V95A reduced the ATPase rate when filaments were saturated with regulatory proteins both in the presence and absence of calcium, indicating either a stabilization of the inactive state or an inability to fully populate the active state. Effects of E180G and D175N were more complex. These two mutations increased ATPase rates at sub-saturating concentrations of troponin and tropomyosin as compared to wild type tropomyosin. At higher concentrations of regulatory proteins, ATPase rates became similar to wild type. Normal activation was achieved with the tight-binding myosin analog N-ethylmaleimide-S1, at saturating regulatory protein concentrations. These results suggest that the E180G and D175N mutations reduce the affinity of tropomyosin for actin and also destabilize troponin binding to the actin thin filaments. (C) 2011 Elsevier Inc. All rights reserved.