The Effect of T192M Mutation in Stability of Alpha Dystroglycan: Study with Molecular Dynamics Simulation

  • Simanti Bhattacharya
  • Amit Das
  • Rakhi Dasgupta
  • Angshuman Bagchi
Conference paper
Part of the Advances in Intelligent Systems and Computing book series (AISC, volume 340)


Alpha-dystroglycan (α-DG), a cell surface receptor links extracellular matrix with cellular cytoskeleton. Its post translational modification is carried out with number of glycosyltransferases, depending on cell types to make the ligand specific mature α-DG receptor protein. However, T192M mutation in α-DG has been found to cause hypo-glycosylation of the protein disabling its Laminin binding form and thereby triggering the onset of a limb girdle muscular dystrophy affecting early childhood. Here for the first time we exploit the effect of this mutation in protein conformational stability. We have found that this mutation leads to significant changes in secondary structure of the protein as well as in the accessible surface area. All these changes also hamper the crucial disulfide bond that is required to maintain the globular fold at the N terminus of α-DG. This molecular insight will therefore be useful for developing new therapeutic approaches to overcome the disease state.


Alpha-dystroglycan Mutation Molecular dynamics simulation Disulfide bond Disease Protein folding 



Alpha dystroglycan


Extra Cellular Matrix


Beta dystroglycan


Dystrophin Associated Protein Complex




Muscular Dystrophy, Dystroglycanopathy, type C9


Optimized potential for liquid simulations all atom force field


Root mean squared deviations


Root mean squared fluctuations


Solvent accessible surface area



The authors are really grateful to the BIF Center, Dept of Biochemistry and Biophysics, University of Kalyani for providing workstation to carry out the experiments. SB and AD also are thankful to UGC, India and CSIR, India for their respective fellowships. The authors would like to acknowledge the ongoing DST-PURSE program 2012-2015 and the DBT (project no. BT/PR6869/BID/7/417/2013) for the support.

Conflict of Interest

The authors declare no conflict of interests.


  1. 1.
    Wang, Y.C., Peterson, S.E., Loring, J.F.: Protein post-translational modifications and regulation of pluripotency in human stem cells. Cell Res. 24, 143–160 (2014)CrossRefGoogle Scholar
  2. 2.
    Ehmsen, J., Poon, E., Davies, K.: The dystrophin-associated protein complex. J. Cell Sci. 115, 2801–2803 (2002)Google Scholar
  3. 3.
    Hara, Y., Kanagawa, M., Kunz, S., Yoshida-Moriguchi, T., Satz, J.S., Kobayashi, Y.M., Zhu, Z., Burden, S.J., Oldstone, M.B., Campbell, K.P.: Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection. Proc. Natl. Acad. Sci. U S A. 108, 17426–17431 (2011)CrossRefGoogle Scholar
  4. 4.
    Kanagawa, M., Saito, F., Kunz, S., Yoshida-Moriguchi, T., Barresi, R., Kobayashi, Y.M., Muschler, J., Dumanski, J.P., Michele, D.E., Oldstone, M.B., Campbell, K.P.: Molecular recognition by LARGE is essential for expression of functional dystroglycan. Cell 117, 953–964 (2004)CrossRefGoogle Scholar
  5. 5.
    Hara, Y., Balci-Hayta, B., Yoshida-Moriguchi, T., Kanagawa, M., Beltrán-Valero de Bernabé, D., Gündeşli, H., Willer, T., Satz, J.S., Crawford, R.W., Burden, S.J., Kunz, S., Oldstone, M.B., Accardi, A., Talim, B., Muntoni, F., Topaloğlu, H., Dinçer, P., Campbell, K.P.: A dystroglycan mutation associated with limb-girdle muscular dystrophy. N. Engl. J. Med. 364, 939–946 (2011)Google Scholar
  6. 6.
    Bhattacharya, S., Das, A., Ghosh, S., Dasgupta, R., Bagchi, A.: Hypoglycosylation of dystroglycan due to T192M mutation: a molecular insight behind the fact. Gene 537, 108–114 (2014)CrossRefGoogle Scholar
  7. 7.
    Bhattacharya, S., Das, A., Dasgupta, R., Bagchi, A.: Dp71 and beta dystroglycan interaction: a molecular modeling approach to understand Duchenne muscular dystrophy. J. Proteins Proteomics 4, 101–107 (2013)Google Scholar
  8. 8.
    Jorgensen, W.L., Tirado-Rives, J.: The OPLS force field for proteins. Energy minimizations for crystals of cyclic peptides and crambin. J. Am. Chem. Soc. 110, 1657–1666 (1988)CrossRefGoogle Scholar
  9. 9.
    Brancaccio, A., Jenö, P., Engel, J.: A single disulfide bridge (Cys182-Cys264) is crucial for alpha-dystroglycan N-terminal domain stability. Ann. N. Y. Acad. Sci. 857, 228–231 (1998)CrossRefGoogle Scholar

Copyright information

© Springer India 2015

Authors and Affiliations

  • Simanti Bhattacharya
    • 1
  • Amit Das
    • 1
  • Rakhi Dasgupta
    • 1
  • Angshuman Bagchi
    • 1
  1. 1.Department of Biochemistry and BiophysicsUniversity of KalyaniKalyani, NadiaIndia

Personalised recommendations