Cardiac troponin T, a sarcomeric AKAP, tethers protein kinase A at the myofilaments.
Cardiac troponin T, a sarcomeric AKAP, tethers protein kinase A at the myofilaments.
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心肌肌钙蛋白 T 是一种肌节 AKAP，将蛋白激酶 A 束缚在肌丝上。
DOI：
10.1074/jbc.m110.148684
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Sumandea,MariusP
中科院分区：
文献类型：
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作者：
Sumandea,CAmelia;Garcia-Cazarin,MaryL;Bozio,CatherineH;Sievert,GailA;Balke,CWilliam;Sumandea,MariusP
Shannamar Dewey，Qian Xu，Susan Nguyen，Aldrin V. Gomes.家族性肥厚型心肌病（FHC）是一组异质性心脏疾病，与肌节蛋白的630多个突变有关。相关疾病的表型、疾病结果和FHC突变的功能后果的分析都表明了一个复杂的发病过程，不能仅通过突变的定位来预测。然而，在皮肤纤维和肌球蛋白ATP酶实验中，与HCM患者相关的突变倾向于增加收缩的钙敏感性。然而，与扩张型心肌病（DCM）相关的突变通常与收缩的钙敏感性降低有关。这些概括并不适用于所有的FHC突变。心肌收缩和舒张的过程也依赖于肌节单位内复杂的蛋白质-蛋白质相互作用。肌节蛋白相互作用紊乱导致的心肌收缩力改变可能在FHC的发病机制中起关键作用。一些研究涉及一种具有心肌病相关突变的蛋白质的蛋白质-蛋白质相互作用的研究显示，与DCM相比，与HCM相关的不同干扰。在这项研究中，我们研究了几个FHC连锁突变的影响，包括充分研究的突变，如心肌肌钙蛋白T（cTnT）I79 N，R278 C和F110 I使用哺乳动物双杂交系统。对于cTnT F110 I，cTnT与α-原肌球蛋白（Tm）之间的相互作用显着高于野生型cTnT。DCM突变先前已显示增加cTnT对Tm的亲和力。cTnT I79 N和R278 C突变体显示与野生型cTnT相似的Tm亲和力。这些结果表明，一些FHC和DCM突变可能在cTnT-Tm相互作用中显示出相似的变化，而其他突变可能不影响cTnT-Tm相互作用。这项工作得到了NIH资助HL 096819的部分支持。
Shannamar Dewey, Qian Xu, Susan Nguyen, Aldrin V. Gomes. Familial hypertrophic cardiomyopathy (FHC) refers to a heterogeneous group of cardiac diseases linked to over 630 mutations in sarcomeric proteins. Analysis of the phenotype of the associated disease, the disease outcome, and the functional consequences of FHC mutations all indicate a complex process of pathogenesis that cannot be predicted solely by the localization of the mutation. However, mutations linked to HCM patients tend to increase the calcium sensitivity of contraction in skinned fiber and myosin ATPase experiments. Mutations linked to dilated cardiomyopathy (DCM), however, are commonly associated with a decrease in calcium sensitivity of contraction. These generalizations do not hold true for all FHC mutations. The process of myocardial contraction and relaxation also depends on complex protein-protein interactions within the sarcomeric unit. Altered myocardial contractility resulting from disturbed interaction profiles of sarcomeric proteins may play a critical role in the pathogenesis of FHC. A few studies that have investigated protein-protein interactions involving one protein with a cardiomyopathy-linked mutation show distinct disturbances associated with HCM as compared to DCM. In this study, we investigated the effects of several FHC linked mutations, including well-investigated mutations such as cardiac troponin T (cTnT) I79N, R278C and F110I using a mammalian two-hybrid system. The interaction between cTnT and alpha-tropomyosin (Tm) was significantly higher for the cTnT F110I than wild-type cTnT. A DCM mutation has previously been shown to increase the affinity of cTnT for Tm. cTnT I79N and R278C mutants show similar affinity for Tm as wild-type cTnT. These results suggest that some FHC and DCM mutations may show similar changes in cTnT-Tm interactions while other mutations may not affect cTnT-Tm interactions. This work is partly supported by NIH grant HL096819.