Abstract
Current advances in structural biology provide valuable insights into structure–function relationship of membrane transporters by solving crystal structures of bacterial homologs of human transporters. Therefore, scientists consider bacterial transporters as useful structural models for designing of drugs targeted in human diseases. The functional homology between Vibrio parahaemolyticus Na+/galactose transporter (vSGLT) and Na+/glucose cotransporter SGLT1 has been well established a decade ago. Now the crystal structure of vSGLT is considered quite valuable in explaining not only the cotransport mechanisms, but it also acts as a representative protein in understanding the protein stability and amino acid interactions within the core structure. We investigated the molecular mechanisms of genetic variations in SGLT1 that cause glucose–galactose malabsorption (GGM) defects using the crystal structure of vSGLT as a model sugar transporter. Our in silico mutagenesis and modeling analysis suggest that the GGM genetic variations lead to conformational changes either by structure destabilization or by formation of unnecessary interaction within the core structure of SGLT1 thereby explaining the genetic defects in Na+ dependent sugar translocation across the cell membrane.
Similar content being viewed by others
References
Faham, S., Watanabe, A., Besserer, G. M., Cascio, D., Specht, A., Hirayama, B. A., et al. (2008). The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. Science, 321, 810–814.
Wright, E. M., & Turk, E. (2004). The sodium/glucose cotransport family SLC5. Pflügers Archiv, 447, 510–518.
Turk, E., & Wright, E. M. (1997). Membrane topology motifs in the SGLT cotransporter family. Journal of Membrane Biology, 159, 1–20.
Banerjee, S. K., McGaffin, K. R., Pastor-Soler, N. M., & Ahmad, F. (2009). SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovascular Research, 84, 111–118.
Martin, M. G., Turk, E., Lostao, M. P., Kerner, C., & Wright, E. M. (1996). Defects in Na+/glucose cotransporter (SGLT1) trafficking and function cause glucose–galactose malabsorption. Nature Genetics, 12, 216–220.
Wright, E. M., Loo, D. D., Hirayama, B. A., & Turk, E. (2004). Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology (Bethesda), 19, 370–376.
Taroni, C., Jones, S., & Thornton, J. M. (2000). Analysis and prediction of carbohydrate binding sites. Protein Engineering, 13, 89–98.
Abramson, J., Smirnova, I., Kasho, V., Verner, G., Kaback, H. R., & Iwata, S. (2003). Structure and mechanism of the lactose permease of Escherichia coli. Science, 301, 610–615.
Quiocho, F. A. (1989). Protein–Carbohydrate interactions—basic molecular-features. Pure and Applied Chemistry, 61, 1293–1306.
Wright, E. M., Loo, D. D., & Hirayama, B. A. (2011). Biology of human sodium glucose transporters. Physiological Reviews, 91, 733–794.
Wright, E. M., Turk, E., & Martin, M. G. (2002). Molecular basis for glucose–galactose malabsorption. Cell Biochemistry and Biophysics, 36, 115–121.
Magen, D., Sprecher, E., Zelikovic, I., & Skorecki, K. (2005). A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. Kidney International, 67, 34–41.
Calado, J., Sznajer, Y., Metzger, D., Rita, A., Hogan, M. C., Kattamis, A., et al. (2008). Twenty-one additional cases of familial renal glucosuria: Absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrology, Dialysis, Transplantation, 23, 3874–3879.
Wright, E. M., Hirayama, B. A., & Loo, D. F. (2007). Active sugar transport in health and disease. Journal of Internal Medicine, 261, 32–43.
Lindquist, B., & Meeuwisse, G. W. (1962). Chronic diarrhoea caused by monosaccharide malabsorption. Acta Paediatrica, 51, 674–685.
Laplane, R., Polonovski, C., Lods, J. C., Debray, P., Etienne, M., & Pissarro, B. (1962). Lintolerance aux sucres a transfert intestinal actif–ses rapports avec lintolerance au lactose et le syndrome Coeliaque. Archives Francaises De Pediatrie, 19, 895.
Melin, K., & Meeuwisse, G. W. (1969). Glucose–galactose malabsorption. A genetic study. Acta Paediatrica Scandinavica,188, 19–24.
Abramson, J., & Wright, E. M. (2009). Structure and function of Na(+)-symporters with inverted repeats. Current Opinion in Structural Biology, 19, 425–432.
Sarker, R. I., Ogawa, W., Shimamoto, T., & Tsuchiya, T. (1997). Primary structure and properties of the Na+/glucose symporter (Sg1S) of Vibrio parahaemolyticus. Journal of Bacteriology, 179, 1805–1808.
Sujatha, M. S., & Balaji, P. V. (2004). Identification of common structural features of binding sites in galactose-specific proteins. Proteins, 55, 44–65.
Yamashita, A., Singh, S. K., Kawate, T., Jin, Y., & Gouaux, E. (2005). Crystal structure of a bacterial homologue of Na+/Cl–dependent neurotransmitter transporters. Nature, 437, 215–223.
Raja, M. M., Tyagi, N. K., & Kinne, R. K. (2003). Phlorizin recognition in a C-terminal fragment of SGLT1 studied by tryptophan scanning and affinity labeling. The Journal of Biological Chemistry, 278, 49154–49163.
Xie, Z., Turk, E., & Wright, E. M. (2000). Characterization of the Vibrio parahaemolyticus Na+/Glucose cotransporter. A bacterial member of the sodium/glucose transporter (SGLT) family. The Journal of Biological Chemistry, 275, 25959–25964.
Oulianova, N., Falk, S., & Berteloot, A. (2001). Two-step mechanism of phlorizin binding to the SGLT1 protein in the kidney. Journal of Membrane Biology, 179, 223–242.
Tyagi, N. K., Kumar, A., Goyal, P., Pandey, D., Siess, W., & Kinne, R. K. (2007). d-Glucose-recognition and phlorizin-binding sites in human sodium/d-glucose cotransporter 1 (hSGLT1): A tryptophan scanning study. Biochemistry, 46, 13616–13628.
Kasahara, M., Maeda, M., Hayashi, S., Mori, Y., & Abe, T. (2001). A missense mutation in the Na+/glucose cotransporter gene SGLT1 in a patient with congenital glucose–galactose malabsorption: Normal trafficking but inactivation of the mutant protein. Biochimica Et Biophysica Acta-Molecular Basis of Disease, 1536, 141–147.
Monne, M., Nilsson, I., Johansson, M., Elmhed, N., & von Heijne, G. (1998). Positively and negatively charged residues have different effects on the position in the membrane of a model transmembrane helix. Journal of Molecular Biology, 284, 1177–1183.
Raja, M. (2011). The potassium channel KcsA: A model protein in studying membrane protein oligomerization and stability of oligomeric assembly? Archives of Biochemistry and Biophysics, 510, 1–10.
Ozdirekcan, S., Nyholm, T. K., Raja, M., Rijkers, D. T., Liskamp, R. M., & Killian, J. A. (2008). Influence of trifluoroethanol on membrane interfacial anchoring interactions of transmembrane alpha-helical peptides. Biophysical Journal, 94, 1315–1325.
Hediger, M. A., Coady, M. J., Ikeda, T. S., & Wright, E. M. (1987). Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature, 330, 379–381.
Elsas, L. J. (1970). Glucose reabsorption in familial renal glycosuria and glucose–galactose malabsorption. Birth Defects Original Article Series, 6, 21–22.
Wright, E. M. (1998). Genetic disorders of membrane transport I. Glucose galactose malabsorption. American Journal of Physiology-Gastrointestinal and Liver Physiology, 275, G879–G882.
Diez-Sampedro, A., Wright, E. M., & Hirayama, B. A. (2001). Residue 457 controls sugar binding and transport in the Na(+)/glucose cotransporter. The Journal of Biological Chemistry, 276, 49188–49194.
Mackenzie, B., Panayotova-Heiermann, M., Loo, D. D., Lever, J. E., & Wright, E. M. (1994). SAAT1 is a low affinity Na+/glucose cotransporter and not an amino acid transporter. A reinterpretation. The Journal of Biological Chemistry, 269, 22488–22491.
Conflict of Interest
None.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Raja, M., Kinne, R.K.H. Structural Insights into Genetic Variants of Na+/Glucose Cotransporter SGLT1 Causing Glucose–Galactose Malabsorption: vSGLT as a Model Structure. Cell Biochem Biophys 63, 151–158 (2012). https://doi.org/10.1007/s12013-012-9352-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12013-012-9352-3