Structural Alterations of Lamin A Protein in Dilated Cardiomyopathy

详细信息    查看全文

• 作者：Pritha Bhattacharjee ; Avinanda Banerjee ; Amrita Banerjee ; Dipak Dasgupta ; Kaushik Sengupta
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：June 18, 2013
• 年：2013
• 卷：52
• 期：24
• 页码：4229-4241
• 全文大小：575K
• 年卷期：v.52,no.24(June 18, 2013)
• ISSN：1520-4995

文摘

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 伪-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.