Structural Alterations of Lamin A Protein in Dilated Cardiomyopathy
Structural Alterations of Lamin A Protein in Dilated Cardiomyopathy
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DOI：
10.1021/bi400337t
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发表时间：
2013-06-18
期刊：
影响因子：
2.9
通讯作者：
Sengupta, Kaushik
中科院分区：
文献类型：
--
作者：
Bhattacharjee, Pritha;Banerjee, Avinanda;Sengupta, Kaushik
Lamin A 蛋白由 LMNA 基因编码，属于 V 型中间丝蛋白家族，是包括人类在内的高等后生动物的主要核蛋白成分。核纤层蛋白 A 和 B 型核纤层蛋白通过形成紧密贴合内核膜的核纤层，赋予细胞核结构刚性，并且在细胞核内部也以丝状网络形式存在。 LMNA 基因中逐渐发现了导致人类至少 11 种多种疾病（统称为核纤层蛋白病）的大量突变。扩张型心肌病（DCM）就是这样一种核纤层病，其中心室扩张导致收缩压和舒张压增加，导致心律失常并最终导致心肌梗塞。核纤层蛋白 A 蛋白中的点突变跨越了该蛋白的整个长度，其中稍占优势的是中央 α 螺旋卷曲螺旋形成结构域。在这项工作中，我们重点关注了之前在患有扩张型心肌病（DCM）的患者中观察到的三种重要突变，这些突变产生了严重的症状。这是第一份表明这些突变导致蛋白质二级和三级结构发生显着改变的报告，从而扰乱核纤层蛋白 A 蛋白的内在自关联行为。野生型和突变体伴随去寡聚过程的焓变化的比较表明它们自缔合的能量学上的差异。转染细胞的细胞核内形成的不同大小和分布的聚集体的形成进一步证实了这一点。
Lamin A protein, encoded by the LMNA gene, belongs to the type V intermediate filament protein family and is a major nuclear protein component of higher metazoan organisms, including humans. Lamin A along with B-type lamins impart structural rigidity to the nucleus by forming a lamina that is closely apposed to the inner nuclear membrane and is also present as a filamentous network in the interior of the nucleus. A vast number of mutations that lead to a diverse array of at least 11 diseases in humans, collectively termed laminopathies, are being gradually uncovered in the LMNA gene. Dilated cardiomyopathy (DCM) is one such laminopathy in which ventricular dilation leads to an increase in systolic and diastolic volumes, resulting in cardiac arrhythmia and ultimately myocardial infarction. The point mutations in lamin A protein span the entire length of the protein, with a slight preponderance in the central alpha-helical coiled-coil forming domain. In this work, we have focused on three such important mutations that had been previously observed in DCM-afflicted patients producing severe symptoms. This is the first report to show that these mutations entail significant alterations in the secondary and tertiary structure of the protein, hence perturbing the intrinsic self-association behavior of lamin A protein. Comparison of the enthalpy changes accompanying the deoligomerization process for the wild type and the mutants suggests a difference in the energetics of their self-association. This is further corroborated by the formation of the aggregates of different size and distribution formed inside the nuclei of transfected cells.