Facilitated cross-bridge interactions with thin filaments by familial hypertrophic cardiomyopathy mutations in α-tropomyosin.
Facilitated cross-bridge interactions with thin filaments by familial hypertrophic cardiomyopathy mutations in α-tropomyosin.
复制标题
α-原肌球蛋白家族性肥厚型心肌病突变促进了与细丝的跨桥相互作用。
DOI：
10.1155/2011/435271
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发表时间：
2011
影响因子：
--
通讯作者：
Chase,PBryant
中科院分区：
文献类型：
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作者：
Wang,Fang;Brunet,NicolasM;Grubich,JustinR;Bienkiewicz,EwaA;Asbury,ThomasM;Compton,LisaA;Mihajlović,Goran;Miller,VictorF;Chase,PBryant
家族性肥厚性心肌病（FHC）是一种心肌肌瘤疾病。为了确定FHC病理的分子机制，利用常规和改进的体外运动测定和圆二色光谱，研究了重组α - Tm中三个FHC相关突变（V95A， D175N和E180G）的功能和结构差异。突变体Tm的α -螺旋结构减少，无序结构增加。当细丝被调节蛋白完全占据时，pca9几乎没有运动，所有原肌球蛋白的最大运动速度（pca5）相似。Ca2+响应性通过增加pca50 （V95A）、降低协同性（D175N）或两者同时增加（E180G）来提高丝滑动速度。当温度升高时，添加了E180G的细丝在温度低于WT ~10℃且更接近体温时表现出失调。当HMM密度降低时，添加了D175N的细丝需要更少的电机来启动滑动或达到最大滑动速度。
Familial hypertrophic cardiomyopathy (FHC) is a disease of cardiac sarcomeres. To identify molecular mechanisms underlying FHC pathology, functional and structural differences in three FHC‐related mutations in recombinantα‐Tm (V95A, D175N, and E180G) were characterized using both conventional and modified in vitro motility assays and circular dichroism spectroscopy. Mutant Tm′s exhibited reducedα‐helical structure and increased unordered structure. When thin filaments were fully occupied by regulatory proteins, little or no motion was detected at pCa 9, and maximum speed (pCa 5) was similar for all tropomyosins. Ca2+‐responsiveness of filament sliding speed was increased either by increasedpCa50(V95A), reduced cooperativityn(D175N), or both (E180G). When temperature was increased, thin filaments with E180G exhibited dysregulation at temperatures ~10°C lower, and much closer to body temperature, than WT. When HMM density was reduced, thin filaments with D175N required fewer motors to initiate sliding or achieve maximum sliding speed.