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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
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
References
Henry MD, Campbell KP (1999) Dystroglycan inside and out. Curr Opin Cell Biol 11:602–607. http://dx.doi.org/10.1016/S0955-0674(99)00024-1
Pollard TD (1986) Mechanism of actin filament self-assembly and regulation of the process by actin-binding proteins. Biophys J 49:149–151. http://dx.doi.org/10.1016/S0006-3495(86)83630-X
Cheever TR, Ervasti JM (2013) Actin isoforms in neuronal development and function. Int Rev Cell Mol Biol 301:157–213. http://dx.doi.org/10.1016/B978-0-12-407704-1.00004-X
Henry MD, Campbell KP (1996) Dystroglycan: an extracellular matrix receptor linked to the cytoskeleton. Curr Opin Cell Biol 8:625–631. http://dx.doi.org/10.1016/S0955-0674(96)80103-7
Dinçer P, Balci B, Yuva Y, Talim B et al (2003) A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan. Neuromuscul Disord 13:771–778. http://dx.doi.org/10.1016/S0960-8966(03)00161-5
Bhattacharya S, Das A, Ghosh S, Dasgupta R, Bagchi A (2014) Hypoglycosylation of dystroglycan due to T192M mutation: a molecular insight behind the fact. Gene 537:108–114. http://dx.doi.org/10.1016/j.gene.2013.11.071
Spiropoulou CF, Kunz S, Rollin PE et al (2002) New world arenavirus clade C, but not clade A and B viruses, utilizes alpha-dystroglycan as its major receptor. J Virol 76:5140–5146
Oldstone MB, Campbell KP (2011) Decoding arenavirus pathogenesis: essential roles for alpha-dystroglycan-virus interactions and the immune response. Virology 411:170–179. http://dx.doi.org/10.1016/j.virol.2010.11.023
Lapošová K, Pastoreková S, Tomášková J, Lymphocytic choriomeningitis virus: invisible but not innocent. Acta Virol 57:160–170. http://dx.doi.org/10.4149/av_2013_02_160
Kunz S, Sevilla N, McGavern DB et al (2001) Molecular analysis of the interaction of LCMV with its cellular receptor [alpha]-dystroglycan. J Cell Biol 155:301–310. http://dx.doi.org/10.1083/jcb.200104103
Shi J, Blundell TL, Mizuguchi K (2001) FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure- dependent gap penalties. J Mol Biol 310:243–257. http://dx.doi.org/10.1006/jmbi.2001.4762
Berman HM (2008) The protein data bank: a historical perspective. Acta Crystallogr A 64:88–95. http://dx.doi.org/10.1107/S0108767307035623
Altschul SF, Gish W, Miller W et al (1990) Basic local alignment search tool. J Mol Biol 215:403–410. http://dx.doi.org/10.1006/jmbi.1990.9999
Pieper U, Webb BM, Barkan DT et al (2011) ModBase, a database of annotated comparative protein structure models, and associated resources, Nucleic Acids Res 39(Database issue):D465–D474. http://dx.doi.org/10.1093/nar/gkq1091
Eisenberg D, Lüthy R, Bowie JU (1997) VERIFY3D: assessment of protein models with three-dimensional profiles. Methods Enzymol 277:396–404. http://dx.doi.org/10.1016/S0076-6879(97)77022-8
Laskowski RA, MacArthur MW, Moss DS et al (1993) PROCHECK—a program to check the stereochemical quality of protein structures. Appl Crystallogr 26:283–291. http://dx.doi.org/10.1107/S0021889892009944
Chen R, Li L, Weng Z, ZDOCK: an initial-stage protein-docking algorithm. Proteins 52:80–87. http://dx.doi.org/10.1002/prot.10389
Jiménez-García B, Pons C, Fernández-Recio J (2013) pyDockWEB: a web server for rigid-body protein-protein docking using electrostatics and desolvation scoring. Bioinformatics 29:1698–1699. http://dx.doi.org/10.1093/bioinformatics/btt262
Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ (2005) PatchDock and SymmDock: servers for rigid and symmetric docking. Nucl Acids Res 33:W363–W367
Brooks BR, Bruccoleri RE, Olafson BD et al (1983) CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem 4:87–217. http://dx.doi.org/10.1002/jcc.540040211
Tina KG, Bhadra R, Srinivasan N (2007) PIC: Protein interactions calculator. Nucleic Acids Res 35(Web Server issue):W473–W476. http://dx.doi.org/10.1093/nar/gkm423
Jaenicke R (1991) Protein stability and molecular adaptation to extreme conditions. Eur J Biochem 202:715–728
The Centre for Food Security and Public Health (2010) Institute for International Co-operation and in Animal Biologics. Iowa State University, Ames. http://www.cfsph.iastate.edu/Factsheets/pdfs/lymphocytic_choriomeningitis.pdf
Pasqual G, Rojek JM, Masin M, Chatton JY, Kunz S (2011) Old world arenaviruses enter the host cell via the multivesicular body and depend on the endosomal sorting complex required for transport. PLoS Pathog 7:e1002232. doi:10.1371/journal.ppat.1002232
Lee AM, Pasquato A, Kunz S (2011) Novel approaches in anti-arenaviral drug development. Virology 411:163–169
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Appendix
Appendix
Rights and permissions
Copyright information
© 2015 The Author(s)
About this chapter
Cite this chapter
Bhattacharya, S., Bhattacharjee, S., Biswas, P.K., Das, A., Dasgupta, R., Bagchi, A. (2015). LCMV Interaction Changes with T192M Mutation in Alpha-Dystroglycan. In: Muppalaneni, N., Gunjan, V. (eds) Computational Intelligence in Medical Informatics. SpringerBriefs in Applied Sciences and Technology(). Springer, Singapore. https://doi.org/10.1007/978-981-287-260-9_2
Download citation
DOI: https://doi.org/10.1007/978-981-287-260-9_2
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-287-259-3
Online ISBN: 978-981-287-260-9
eBook Packages: EngineeringEngineering (R0)