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Disease-Causing Mutation in Extracellular and Intracellular Domain of FGFR1 Protein: Computational Approach

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Abstract

In-depth computationally based structural analysis of human fibroblast growth factor type 1 (FGFR1) protein carrying disease-causing mutation was performed in this study. Gain or loss of function due to missense mutations in FGFR1 is responsible for a variety of disorders including Kallmann syndrome, Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, etc. The mutant model of the human FGFR1 protein was subjected to various in silico analysis, and most deleterious SNPs were screened out. Furthermore, docking and long molecular dynamics simulations were carried out with an intention of studying the possible impact of these mutations on the protein structure and hence its function. Analysis of various structural properties—especially of those of the functionally important regions: the extracellular immunoglobulin domain and intracellular Tyrosine kinase domain—gave some insights into the possible structural characteristics of the disease mutant and the wild-type forms of the protein. In a nutshell, compared to the wild-type protein, the mutant structures V273M and S685F are associated with significant changes, and the functionally important regions seem to adopt such structures that are not conducive for the wild-type-like functionality.

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References

  1. Jiao, H., Arner, P., Dickson, S. L., Vidal, H., et al. (2011). Journal Clinical Endocrinology Metabolism, 96, E962–E966.

    Article  CAS  Google Scholar 

  2. Rodriguez, O. P., Roman, G. J., Vilas, Z. A., Jose, E. S., et al. (2011). British Journal of Haematology, 155, 73–83.

    Article  Google Scholar 

  3. Zhou, Y. X., Pannu, R., Le, T. Q., & Armstrong, R. C. (2012). Neurobiology of Disease, 45, 196–205.

    Article  CAS  Google Scholar 

  4. Bass, A. J., Watanabe, H., Mermel, C. H., Yu, S., Perner, S., et al. (2009). Nature Genetics, 41, 1238–1242.

    Article  CAS  Google Scholar 

  5. Ford, P. M., Abud, H., & Murphy, M. (2001). Clinical and Experiment Pharmacology Physiology, 28, 493–503.

    Article  Google Scholar 

  6. Plotnikov, A. N., Schlessinger, J., Hubbard, S. R., & Mohammadi, M. (1999). Cell, 98, 641–650.

    Article  CAS  Google Scholar 

  7. Dode, C., Levilliers, J., Dupont, J. M., De Paepe, A., et al. (2003). Nature Genetics, 33, 463–465.

    Article  CAS  Google Scholar 

  8. Albuisson, J., Pecheux, C., Carel, J. C., Lacombe, D., et al. (2005). Human Mutation, 25, 98–99.

    Article  Google Scholar 

  9. Raivio, T., Sidis, Y., Plummer, L., Chen, H., et al. (2009). Journal Clinical Endocrinology and Metabolism, 94, 4380–4390.

    Article  CAS  Google Scholar 

  10. Thusberg, J., & Vihinen, M. (2006). Human Mutation, 27, 1230–1243.

    Article  CAS  Google Scholar 

  11. Doss, C. G. P., Rajasekaran, R., Arjun, P., & Sethumadhavan, R. (2010). Interdisciplinary Science, 4, 320–346.

    Article  Google Scholar 

  12. Doss, C. G. P., & Sethumadhavan, R. (2009). Journal Biomedical Science, 24, 16–42.

    Google Scholar 

  13. Rajith, B., & Doss, C. G. P. (2011). PLoS One, 6(9), e24607.

    Article  CAS  Google Scholar 

  14. Doss, C. G. P., & Rajith, B. (2012). PLoS ONE, 7(4), e34573.

    Article  CAS  Google Scholar 

  15. Ng, P. C., & Henikoff, S. (2003). Nucleic Acids, 31, 3812–3814.

    Article  CAS  Google Scholar 

  16. Adzhubei, I. A., Schmidt, S., Peshkin, L., Vasily, E. R., Anna, G., et al. (2010). Nature Methods, 7, 248–249.

    Article  CAS  Google Scholar 

  17. Bromberg, Y., Yachdav, G., & Rost, B. (2008). Bioinformatics, 20, 2397–2398.

    Article  Google Scholar 

  18. Reva, B., Antipin, Y., & Sander, C. (2011). Nucleic Acids Research, 39(17), e118.

    Article  CAS  Google Scholar 

  19. Hicks, S., Wheeler, D. A., Plon, S. E., & Kimmel, M. (2011). Human Mutation, 6, 661–668.

    Article  Google Scholar 

  20. Miller, M. P., & Kumar, S. (2001). Human Molecular Genetics, 10, 2319–2328.

    Article  CAS  Google Scholar 

  21. Mooney S.D., Klein T.E. (2002). BMC Bioinformatics, 3–24.

  22. Shen, B., & Vihinen, M. (2004). Protein Engineering Design Selection, 17, 267–276.

    Article  CAS  Google Scholar 

  23. Vitkup, D., Sander, C., & Church, G. M. (2003). Genome Biology, 4, R72.1–R72.10.

    Article  Google Scholar 

  24. Doniger, S. W., Kim, H. S., Swain, D., Corcuera, D., & Williams, M. (2008). PLoS Genetics, 29(4), e1000183.

    Article  Google Scholar 

  25. Aly, T. A., Eller, E., Ide, A., Gowan, K., Babu, S. R., et al. (2006). Diabetes, 55, 1265–1269.

    Article  CAS  Google Scholar 

  26. Ashkenazy, H., Erez, E., Martz, E., Pupko, T., & Ben-Tal, N. (2010). Nucleic Acids Research, 38, 529–533.

    Article  Google Scholar 

  27. Schweers, O., Schonbrunn-Hanebeck, E., Marx, A., & Mandelkow, E. (1994). Journal of Biological Chemistry, 269, 24290–24297.

    CAS  Google Scholar 

  28. Bates, G. (2003). Lancet, 361, 1642–1644.

    Article  CAS  Google Scholar 

  29. Grateau, G., Verine, J., Delpech, M., & Ries, M. (2005). Medical Science (Paris), 21, 627–633.

    Article  Google Scholar 

  30. Linding, R., Schymkowitz, J., Rousseau, F., Diella, F., & Serrano, L. (2004). Journal of Molecular Biology, 342, 345–353.

    Article  CAS  Google Scholar 

  31. Maurer-Stroh, S., Debulpaep, M., Kuemmerer, N., de la Lopez, P. M., Martins, I. C., et al. (2010). Nature Methods, 7, 237–242.

    Article  CAS  Google Scholar 

  32. Conchillo-Sole, O., de Groot, N. S., Aviles, F. X., Vendrell, J., Daura, X., et al. (2007). BMC Bioinformatics, 8, 65.

    Article  Google Scholar 

  33. Capriotti, E., Fariselli, P., Rossi, I., & Casadio, R. (2008). BMC Bioinformatics, 9(Suppl 2), S6.

    Article  Google Scholar 

  34. Kwasigroch, J. M., Gilis, D., Dehouck, Y., & Rooman, M. (2002). Bioinformatics, 18, 1701–1702.

    Article  CAS  Google Scholar 

  35. Khan, S., & Vihinen, M. (2010). Human Mutation, 31, 675–678.

    Article  CAS  Google Scholar 

  36. Parthiban, V., Gromiha, M. M., Abhinandan, M., & Schomburg, D. (2007). BMC Structural Biology, 7, 54.

    Article  Google Scholar 

  37. Dosztanyi, Z., Magyar, C., Tusnady, G., & Simon, I. (2003). Bioinformatics, 19, 899–900.

    Article  CAS  Google Scholar 

  38. Magyar, C., Gromiha, M. M., Pujadas, G., Tusnady, G. E., & Simon, I. (2005). Nucleic Acids Research, 33, W303–W305.

    Article  CAS  Google Scholar 

  39. Dosztanyi, Z., Fiser, A., & Simon, I. (1997). Journal of Molecular Biology, 272, 597–612.

    Article  CAS  Google Scholar 

  40. Trarbach, E. B., Costa, E. M. F., Versiani, B., de Castro, M., et al. (2006). Journal Clinical Endocrinology Metabolism, 91, 4006–4012.

    Article  CAS  Google Scholar 

  41. Dode, C., Fouveaut, C., Mortier, G., Janssens, S., et al. (2007). Human Mutation, 28, 97–98.

    Article  Google Scholar 

  42. Pitteloud, N., Meysing, A., Quinton, R., Acierno, J. S., et al. (2006). Molecular Cellular Endocrinology, 254, 60–69.

    Article  Google Scholar 

  43. Greenman, C., Stephens, P., Smith, R., Dalgliesh, G. L., et al. (2007). Nature, 446, 153–158.

    Article  CAS  Google Scholar 

  44. Zenaty, D., Bretones, P., Lambe, C., Guemas, I., et al. (2006). Molecular Cellular Endocrinology, 254, 78–83.

    Article  Google Scholar 

  45. The MGC Project Team. (2004). Genome Research, 14, 2121–2127.

    Article  Google Scholar 

  46. Pitteloud, N., Acierno, J. S., Jr., Meysing, A., Eliseenkova, A. V., et al. (2006). Proceedings of the National Academy of Science of the United States of America, 103, 6281–6286.

    Article  CAS  Google Scholar 

  47. Muenke, M., Schell, U., Hehr, A., Robin, N. H., et al. (1994). Nature Genetics, 8, 269–274.

    Article  CAS  Google Scholar 

  48. Kress, W., Petersen, B., Collmann, H., Grimm, T., et al. (2000). Cytogenet. Cell Genetics, 91, 138–140.

    Article  CAS  Google Scholar 

  49. White, K. E., Cabral, J. M., Davis, S. I., Fishburn, T., et al. (2005). American Journal of Human Genetics, 76, 361–367.

    Article  CAS  Google Scholar 

  50. Sato, N., Hasegawa, T., Hori, N., Fukami, M., et al. (2005). Human Reproduction, 20, 2173–2178.

    Article  Google Scholar 

  51. Nosoh, Y., Sekiguchi, T. (1991). Ellis Horwood Limited.

  52. Richmond, T. J. (1984). Journal of Molecular Biology, 178, 63–89.

    Article  CAS  Google Scholar 

  53. DeLano, W.L. (2002). CA, USA.

  54. Bae, J. H., Lew, E. D., Yuzawa, S., Tomé, F., Lax, I., et al. (2009). Cell, 138, 514–524.

    Article  CAS  Google Scholar 

  55. Lindahl, E., Azuara, C., Koehl, P., & Delarue, M. (2006). Nucleic Acids Research, 3, W52–W56.

    Article  Google Scholar 

  56. Delarue, M., & Dumas, P. (2004). Proceedings of the National Academy of Sciences of the United States of America, 101, 6957–6962.

    Article  CAS  Google Scholar 

  57. Guex, N., & Peitsch, M. C. (1997). Electrophoresis, 18, 2714–2723.

    Article  CAS  Google Scholar 

  58. Davis, I. W., Leaver-Fay, A., Chen, V. B., & Block, J. N. (2007). Nucleic Acids Research, 35, W375–W383.

    Article  Google Scholar 

  59. Dominguez, C., Boelens, R., & Bonvin, A. M. (2003). Journal of the American Chemical Society, 125, 1731–1737.

    Article  CAS  Google Scholar 

  60. de Vries, S. J., Dijk, M. V., & Bonvin, A. M. J. J. (2010). Nature Protocols, 5, 883–897.

    Article  Google Scholar 

  61. Nilges, M. (1995). Journal of Molecular Biology, 245, 645–660.

    Article  CAS  Google Scholar 

  62. Nilges, M., Macias, M. J., O’Donoghue, S. I., & Oschkinat, H. (1997). Journal of Molecular Biology, 269, 408–422.

    Article  CAS  Google Scholar 

  63. Brunger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., et al. (1998). Acta Crystallographica Section D: Biological Crystallography, 54, 905–921.

    Article  CAS  Google Scholar 

  64. Sakaki, M., Koike, H., Takahashi, N., Sasagawa, N., Tomioka, S., et al. (2001). Journal of Biochemistry, 129, 321–332.

    Article  CAS  Google Scholar 

  65. Hess, B., Kutzner, C., van der Spoel, D., & Lindahl, E. (2008). Journal Chemistry Theory Computer, 4, 435–447.

    Article  CAS  Google Scholar 

  66. Van, G.W.F., Billeter, S.R., Eising, A.A., Hunenberger, P.H. et al. (1996). Zurich, Groningen.

  67. Essmann, U., Perera, L., Berkowitz, M. L., Darden, T., Lee, H., et al. (1995). The Journal of Chemical Physics, 103, 8577–8593.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors take this opportunity to thank the management of Vellore Institute of Technology University for providing the facilities and encouragement to carry out this work.

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Correspondence to C. George Priya Doss.

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Rajith, B., George Priya Doss, C. Disease-Causing Mutation in Extracellular and Intracellular Domain of FGFR1 Protein: Computational Approach. Appl Biochem Biotechnol 169, 1659–1671 (2013). https://doi.org/10.1007/s12010-012-0061-6

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