Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore, 632014 Tamil Nadu, India.
Amino Acids. 2012 Aug;43(2):603-15. doi: 10.1007/s00726-011-1108-7. Epub 2011 Oct 12.
Lamin A/C proteins are the major components of a thin proteinaceous filamentous meshwork, the lamina, that underlies the inner nuclear membrane. A few specific mutations in the lamin A/C gene cause a disease with remarkably different clinical features: FPLD, or familial partial lipodystrophy (Dunnigan-type), which mainly affects adipose tissue. Lamin A/C mutant R482W is the key variant that causes FPLD. Biomolecular interaction and molecular dynamics (MD) simulation analysis were performed to understand dynamic behavior of native and mutant structures at atomic level. Mutant lamin A/C (R482W) showed more interaction with its biological partners due to its expansion of interaction surface and flexible nature of binding residues than native lamin A/C. MD simulation clearly indicates that the flexibility of interacting residues of mutant are mainly due to less involvement in formation of inter and intramolecular hydrogen bonds. Our analysis of native and Mutant lamin A/C clearly shows that the structural and functional consequences of the mutation R482W causes FPLD. Because of the pivotal role of lamin A/C in maintaining dynamics of nuclear function, these differences likely contribute to or represent novel mechanisms in laminopathy development.
核层蛋白 A/C 是薄的蛋白丝状网的主要成分，该网位于核内层膜的下面。核层蛋白 A/C 基因的少数特定突变会导致具有明显不同临床特征的疾病：家族性部分脂肪营养不良（Dunnigan 型），主要影响脂肪组织。核层蛋白 A/C 突变 R482W 是导致 FPLD 的关键变体。进行了生物分子相互作用和分子动力学（MD）模拟分析，以在原子水平上了解天然和突变结构的动态行为。与天然核层蛋白 A/C 相比，突变核层蛋白 A/C（R482W）由于其相互作用表面的扩展和结合残基的柔性，与生物伴侣的相互作用更多。MD 模拟清楚地表明，突变体相互作用残基的灵活性主要是由于它们较少参与形成分子间和分子内氢键。我们对天然和突变核层蛋白 A/C 的分析清楚地表明，突变 R482W 导致 FPLD 的结构和功能后果。由于核层蛋白 A/C 在维持核功能动力学方面的关键作用，这些差异可能有助于或代表着核纤层病发展中的新机制。
