LCMV Interaction Changes with T192M Mutation in Alpha-Dystroglycan

  • Simanti Bhattacharya
  • Sanchari Bhattacharjee
  • Prosun Kumar Biswas
  • Amit Das
  • Rakhi Dasgupta
  • Angshuman Bagchi
Chapter
Part of the SpringerBriefs in Applied Sciences and Technology book series (BRIEFSAPPLSCIENCES)

Abstract

Limb girdle muscular dystrophy (OMIM: 613818) is a severe disease in humans, which broadly affects brain development. The disease is caused by T192M mutation in the protein alpha-dystroglycan (α-DG). α-DG is an important component of dystrophin–dystroglycan complex which links extracellular matrices with actin cytoskeleton and thereby maintains signalling cascades essential for the development of tissues and organs. The mutation T192M in α-DG hampers proper glycosylation of α-DG thereby developing limb girdle muscular dystrophy. Prototype virus for Old World Arenaviruses (OWV), Lymphocytic Choriomeningitis virus (LCMV) also uses this α-DG as host cell receptor and invades the host cell causing a disease called Lymphocytic choriomeningitis, an infection to meninges. Thereby, interaction of α-DG and LCMV has become an interesting object of study to predict the mode of the disease onset. In our current work, we have used homology modelling, molecular docking and molecular dynamics (MD) with temperature variation. We have identified significant structural differences between wild type (WT) and mutant (MT) α-DG in terms of spatiotemporal orientations of amino acids. This change in the folding patterns of the WT and MT α-DG has brought forth a different interaction pattern of the WT and MT α-DG with GP1 protein from LCMV as reflected in our docking simulations. Further MD simulations with the complexes over tropical and temperate environment have revealed that MT-α-DG-LCMV GP1 complex is relatively more stable than the wild type counterpart. It has also been found that LCMV GP1 has interacted strongly with mutant α-DG. Our studies therefore has shed light on the structure and molecular interaction pattern of LCMV with MT α-DG and also indicate a possibility of T192M mutant in α-DG making the receptor to interact strongly with LCMV GP1. These insights also provide clues to develop possible therapeutic approaches.

Keywords

Homology modelling Molecular dynamics Limb girdle muscular dystrophy Viral infection-drug design 

Abbreviations

DG

Dystroglycan

MDDGC9

Muscular Dystrophy, Dystroglycanopathy, Type C9

OMIM

Online Mendelian Inheritance in Man

PDB

Protein Data Bank

RMSD

Root Mean Square Deviation

WT

Wildtype

MT

Mutated

Notes

Acknowledgments

Authors are thankful to Dept of Biochemistry and Biophysics, University of Kalyani for their continuous support and for providing the necessary instruments to carry out the experiments. The authors would like to thank the ongoing DST-PURSE programme. SB and AD also are thankful to UGC, India and CSIR, India for their respective fellowships, and the DBT (project no. BT/PR6869/BID/7/417/2012) for the necessary infrastructural support.

Conflict of Interest

The authors declare no conflict of interest.

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Copyright information

© The Author(s) 2015

Authors and Affiliations

  • Simanti Bhattacharya
    • 1
  • Sanchari Bhattacharjee
    • 1
  • Prosun Kumar Biswas
    • 1
  • Amit Das
    • 1
  • Rakhi Dasgupta
    • 1
  • Angshuman Bagchi
    • 1
  1. 1.Department of Biochemistry and BiophysicsUniversity of KalyaniNadiaIndia

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