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In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A/C protein

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Abstract

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.

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Acknowledgments

We gratefully acknowledge the management of Vellore Institute of Technology University for providing the facilities to carry out this work. We thank the anonymous reviewers for their helpful comments and critical reading of the manuscript.

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  1. Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore, 632014, Tamil Nadu, India

    Vidya Rajendran, Rituraj Purohit & Rao Sethumadhavan

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  1. Vidya Rajendran
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Rajendran, V., Purohit, R. & Sethumadhavan, R. In silico investigation of molecular mechanism of laminopathy caused by a point mutation (R482W) in lamin A/C protein. Amino Acids 43, 603–615 (2012). https://doi.org/10.1007/s00726-011-1108-7

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