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首页> 外文期刊>Biochemistry >Long-range effects of familial hypertrophic cardiomyopathy mutations E180G and D175N on the properties of tropomyosin
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Long-range effects of familial hypertrophic cardiomyopathy mutations E180G and D175N on the properties of tropomyosin

机译：家族性肥厚性心肌病突变E180G和D175N对原肌球蛋白特性的远程影响

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Cardiac α-tropomyosin (Tm) single-site mutations D175N and E180G cause familial hypertrophic cardiomyopathy (FHC). Previous studies have shown that these mutations increase both Ca ~(2+) sensitivity and residual contractile activity at low Ca ~(2+) concentrations, which causes incomplete relaxation during diastole resulting in hypertrophy and sarcomeric disarray. However, the molecular basis for the cause and the difference in the severity of the manifested phenotypes of disease are not known. In this work we have (1) used ATPase studies using reconstituted thin filaments in solution to show that these FHC mutants result in an increase in Ca ~(2+) sensitivity and an increased residual level of ATPase, (2) shown that both FHC mutants increase the rate of cleavage at R133, ～45 residues N-terminal to the mutations, when free and bound to actin, (3) shown that for Tm-E180G, the increase in the rate of cleavage is greater than that for D175N, and (4) shown that for E180G, cleavage also occurs at a new site 53 residues C-terminal to E180G, in parallel with cleavage at R133. The long-range decreases in dynamic stability due to these two single-site mutations suggest increases in flexibility that may weaken the ability of Tm to inhibit activity at low Ca ~(2+) concentrations for D175N and to a greater degree for E180G, which may contribute to differences in the severity of FHC.
机译：心脏α-原肌球蛋白（Tm）单点突变D175N和E180G引起家族性肥厚性心肌病（FHC）。先前的研究表明，这些突变会在低Ca〜（2+）浓度下增加Ca〜（2+）的敏感性和残留的收缩活性，这会导致舒张期舒张不完全，从而导致肥大和肌节紊乱。然而，原因的分子基础以及所表现出的疾病表型的严重性差异尚不清楚。在这项工作中，我们（1）在溶液中使用重组细丝进行了ATPase研究，以表明这些FHC突变体导致Ca〜（2+）敏感性增加和ATPase残留水平增加，（2）表明这两种FHC突变体增加了R133的切割速率，在突变的N端约有45个残基，当游离并与肌动蛋白结合时（3）表明，对于Tm-E180G，切割速率的增加大于对D175N的切割， （4）显示，对于E180G，切割也发生在E180G C末端的53个残基的新位点，与在R133处的切割平行。由于这两个单点突变，动态稳定性的远距离下降表明柔韧性增加，这可能削弱Tm在低Ca〜（2+）浓度下对D175N抑制活性和在更大程度上对E180G抑制活性的能力。可能会导致FHC严重程度的差异。

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    《Biochemistry》 |2012年第32期|共8页
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    Ly S.; Lehrer S.S.;

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