Browse > Article
http://dx.doi.org/10.5808/GI.2010.8.2.070

In Silico Study of Human Gap Junction Beta-2 Protein by Homology Modeling  

Shehzadi, Abida (Bioinformatics Wing, Center of Excellence in Molecular Biology, University of the Punjab)
Masood, Khalid (Bioinformatics Wing, Center of Excellence in Molecular Biology, University of the Punjab)
Publication Information
Genomics & Informatics / v.8, no.2, 2010 , pp. 70-75 More about this Journal
Abstract
Asp66his, Asp54Lys, and Asp50Asn are mutations in connexin 26 that are observed in the clinic and give rise to autosomal dominant syndromes. They are the result of point mutations in the human gap junction ${\beta}-2$ gene. In order to investigate the structural mechanism of Bart-Pumphrey Syndrome, Keratitis-Ichthyosis-Deafness Syndrome, and Vohwinkel Syndrome, homology modeling was carried out. Asp66 has direct contact with Asn62 by two hydrogen bonds in the wild-type protein, and in Asp66His, the biggest change observed is a tremendous energy increase caused by hydrogen bond breakage to Asn62. Shifts in the side chain and new hydrogen bond formation are observed for Lys54 compared to the wild-type protein (Asn54) and result in closer contact to Val84. Asp50Asn causes a significant decrease in bond energy, and residual charge reversal repels the ion and metabolites and, hence, inhibits their transportation. Such perturbations are likely to be a factor contributing to abnormal functioning of ion channels, resulting cell death and disease.
Keywords
Bart-Pumphrey syndrome; connexin 26; gap junction; ${\beta}-2$ protein; hearing impairment; Keratitis-Ichthyosis-Deafness syndrome; knuckle pads; leukonychia; vohwinkel syndrome;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Sosinsky, G. (1995). Mixing of connexins in gap junction membrane channels. Proc. Natl. Acad. Sci. 92, 9210-9214.   DOI
2 Talley, K., Ng, C., Shoppell, M., Kundrotas, P., and Alexov, E. (2008). On the electrostatic component of protein-protein binding free energy PMC Biophysics 1:2 doi:10.1186/ 1757-5036-1-2. http://www.physmathcentral.com/1757-5036/1/2   DOI
3 Tremblay, K., and Ross, B. (2007). Effects of age and age-related hearing loss on the brain. J. Commun. Disorders 40, 305-312.   DOI
4 Williams, R.W., Chang, A., Juretic, D., and Loughran, S. (1987). Secondary structure predictions and medium range interactions. Biochim Biophys Acta. 916, 200-204.   DOI
5 Xiang, Z. (2006). Advances in homology protein structure modeling. Curr. Protein Pept. Sci . 7, 217-227.   DOI
6 Yotsumoto, S., Hashiguchi, T., Chen, X., Ohtake, N., Tomitaka, A., Akamatsu, H., Matsunaga, K., Shiraishi, S., Miura, H., Adachi, J., and Kanzaki, T. (2003). Novel mutations in GJB2 encoding connexin-26 in Japanese patients with keratitis-ichthyosis-deafness syndrome. Br. J. Dermatol . 148, 649-653.   DOI
7 Zelante, L., Gasparini, P., Estivill, X., Melchionda, S., D'Agruma, L., Govea, N., Mila, M., Monica, M.D., Lutfi, J., Shohat, M., Mansfield E., Delgrosso, K., Rappaport, E., Surrey, S., and Fortina, P. (1997). Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum. Mol. Genet. 6, 1605-1609.   DOI
8 Lattig, M.C., Gelvez, N., Plaza, S.L., Tamayo, G., Uribe, J.I., Salvatierra, I., Bernal, J.E., and Tamayo, M.L. (2008). Deafness on the island of Providencia - Colombia: different etiology, different genetic counseling. Genet. Couns . 19, 403-412.
9 Mahasneh, A.A., and Battah, R.M. (2006). Prevalence of connexin 26 mutations in patients from jordan with non syndromic hearing loss. Int. J. Hum. Genet. 6, 119-124.   DOI
10 Lautermann, J., ten Cate, W.J., Altenhoff, P., Grummer, R., Traub, O., Frank, H., Jahnke, K., and Winterhager, E. (1998). Expression of the gap-junction connexins 26 and 30 in the rat cochlea. Cell Tissue Res . 294, 415-420.   DOI
11 Maestrini, E., Korge, P.B., Ocana-Sierra, J., Calzolari, E., Cambiaghi, S., Scudder, M.P., Hovnanian, A., Monaco, P.A., and Munro, S.C. (1999). A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families. Hum. Mol. Genet. 8, 1237- 1243.   DOI
12 Marziano, K.N., Casalotti, O.S., Partelli, E.A., Becker, L.D., and Forage, A. (2003). Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Hum. Mole. Genet . 12, 805-812.   DOI
13 Musil, L.S., and Goodenough, D.A. (1993). Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER. Cell 74, 1065-1077.   DOI
14 Richard, G., Brown, N., Ishida-Yamamoto, A., and Krol, A. (2004). Expanding the phenotypic spectrum of Cx26 disorders: bart-pumphrey syndrome is caused by a novel missense mutation in GJB2. J. Invest. Dermatol . 123, 856- 863.   DOI
15 Saez, J.C., Branes. M.C., Corvalan, L.A., Eugenin, E.A., Gonzalez, H., Martinez, A.D., and Palisson, F. (2000). Gap junctions in cells of immune system: structure, regulation and possible functional roles. Braz. J. Med. Biol. Res . 33, 447-455.   DOI
16 Snoeckx, L.R., Hassan, M.D., Kamal, M.N., Bogaert, D.V.K., and Camp, V.G. (2005). Mutation analysis of the GJB2 (connexin 26) gene in egypt. J. Hum. Mut. 26, 60-61.
17 Forge, A., Becker, D., Casalotti, S., Edwards, J., Marziano, N., and Nickel, R. (2002). Connexins and gap junctions in the inner ear. Audiol. Neurootol. 7, 141-145.   DOI
18 Castillo, J.F., Rodriguez-Ballesteros, M., A'lvarez, A., Hutchin, T., Leonardi, E., Oliveira, A.C., Azaiez, H., Brownstein, Z., Avenarius, R.M., Marlin, S., Pandya, A., Shahin, H., Siemering, R.K., Weil, D., Wuyts, W., Aguirre, A.L., Martin,Y., Moreno-Pelayo, A.M., Villamar, M., Avraham, B.K., Dahl, M.H., Kanaan, M., Nance, E.W., Petit, C., Smith, H.J.R., Camp, V.G., Sartorato, L.E., Murgia, A., Moreno, F., and Castillo, I. (2005). A novel deletion involving the connexin-30 gene, del (GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J. Med. Genet . 42, 588-594.   DOI
19 Denoyelle, F., Lina-Granade, G., Plauchu, H., Bruzzone, R., Chaib, H., Levi-Acobas, F., Weil, D., and Petit, C. (1998). Connexin 26 gene linked to a dominant deafness. Nature 393, 319-320.   DOI
20 Eyken, V.E., Camp, V.G., and Laer, V.L. (2007). The Complexity of age-related hearing impairment: contributing environmental and genetic factors. Audiol. Neurotol. 12, 345-358.   DOI
21 Karaguler, G.N., Sessions, B.R., Moreton, M. K., Clarke, R. A., and Holbrook, J.J. (2004). Estimating the energetic contribution of hydrogen bonding to the stability of Candida methylica formate dehydrogenase by using double mutant cycle. Biotechnol. Lett. 26, 1137-1140.   DOI
22 Kelsell, D.P., Dunlop, J., Stevens, H.P., Lench, N., Liang, J.N., Parry, G., Mueller, R.F., and Leigh, I.M. (1997). Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387, 80-83.   DOI
23 Laer, V.L., Coucke, P., Mueller, F.R., Caethoven, G., Flothmann, K., Prasad, D.S., Chamberlin, P.G., Houseman, M., Taylor, R.G., Heyning, V.M.C., Fransen, E., Rowland, J., Cucci, A.R., Smith, H.J.R., and Camp, V.G. (2001). A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment. J. Med. Genet. 38, 515-518.   DOI
24 Bitner-Glindzicz, M. (2002). Hereditary deafness and phenotyping in humans. Br. Med. Bull. 63, 73-94.   DOI
25 Abe, S., Usami, S., Shinkawa, H., Kelley, M.P., and Kimberling, J.W. (2000). Prevalent connexin 26 gene (GJB2) mutations in Japanese. J. Med. Genet . 37, 41-43.   DOI
26 Bairoch, A., and Apweiler, R. (1997). The SWISS-PROT protein sequence data bank and its supplement TrEMBL. Nucl. Acids Res . 25, 31-36.   DOI
27 Bart, R.S., and Pumphrey, R.E. (1967). Knuckle pads, Leukonychia & Deafness. A Dominantly Inherited Syndrome. N. Engl. J. Med. 276, 202-207.   DOI