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Exploring the Structural Insights on Human Laforin Mutation K87A in Lafora Disease—A Molecular Dynamics Study

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Abstract

Lafora disease (LD) is an autosomal recessive, progressive form of myoclonus epilepsy which affects worldwide. LD occurs mainly in countries like southern Europe, northern Africa, South India, and in the Middle East. LD occurs with its onset mainly in teenagers and leads to decline and death within 2 to 10 years. The genes EPM2A and EPM2B are commonly involved in 90 % of LD cases. EPM2A codes for protein laforin which contains an amino terminal carbohydrate binding module (CBM) belonging to the CBM20 family and a carboxy terminal dual specificity phosphatase domain. Mutations in laforin are found to abolish glycogen binding and have been reported in wet lab methods. In order to investigate on structural insights on laforin mutation K81A, we performed molecular dynamics (MD) simulation studies for native and mutant protein. MD simulation results showed loss of stability due to mutation K87A which confirmed the structural reason for conformational changes observed in laforin. The conformational change of mutant laforin was confirmed by analysis using root mean square deviation, root mean square fluctuation, solvent accessibility surface area, radius of gyration, hydrogen bond, and principle component analysis. Our results identified that the flexibility of K87A mutated laforin structure, with replacement of acidic amino acid to aliphatic amino acid in functional CBM domain, have more impact in abolishing glycogen binding that favors LD.

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Authors and Affiliations

  1. Unit of Psychiatry, Faculty of Medicine, AIMST University, Bedong, 08100, Kedah, Malaysia

    P. S. Srikumar

  2. Unit of Biochemistry, Faculty of Medicine, AIMST University, Bedong, Kedah, Malaysia

    K. Rohini

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  1. P. S. Srikumar
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  2. K. Rohini
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Correspondence to P. S. Srikumar.

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Srikumar, P.S., Rohini, K. Exploring the Structural Insights on Human Laforin Mutation K87A in Lafora Disease—A Molecular Dynamics Study. Appl Biochem Biotechnol 171, 874–882 (2013). https://doi.org/10.1007/s12010-013-0393-x

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  • DOI: https://doi.org/10.1007/s12010-013-0393-x

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