Abstract
A sequence comparison of the two membrane-associated (MA) domains of the cystic fibrosis transmembrane conductance regulator (CFTR), multidrug resistance transporter (MDR), and α-factor pheromone export system (STE6) proteins, each of which are believed to contain a total of 12 transmembrane (TM) segments, reveals significant amino acid homology and length conservation in the loop regions that connect individual TM sequences. Similar structural homology is observed between these proteins, hemolysin B (HLYB) and the major histocompatibility-linked peptide transporter, HAM1, the latter two which contain a single MA domain composed of six TM segments. In addition, there are specific sequences that are conserved within the TM segments of the five different membrane proteins. This observation suggests that the folding topologies of the MA domains of MDR, STE6, and CFTR in the plasma membrane are likely to be very similar. The sequence analysis also reveals that there are three characteristic motifs (a pair of aromatic residues, LTLXXXXXXP and GXXL) that are conserved in MDR, STE6, HLYB, HAM1, but not in CFTR. We propose that although CFTR may be evolutionarily related to these other membrane proteins, it belongs to a separate subclass.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anderson, M. P., Gregory, R. J., Thompson, S., Souza, D. W., Paul, S., Mulligan, R. C., Smith, A. E., and Welsh, M. J. (1991).Science 253, 202–205.
Boat, T., Welsh, M., and Beaudet, A. (1989). InThe Metabolic Basis of Inherited Diseases (Scriver, C., Beaudet, A., Sly, W., and Valie, D., eds.), McGraw-Hill, New York, pp. 2649–2680.
Bradley, G., Juranka, P. F., and Ling, V. (1988).Biochim. Biophys. Acta 948, 87–128.
Cangelosi, G. A., Martinetti, G., Leigh, J. A., Lee, C. C., Theines, C., and Nester, E. W. (1989).J. Bacteriol. 171, 1609–1615.
Chen, C.-J., Chin, J. E., Ueda, K., Clark, D. P., Pastan, I., Gottesman, M. M., and Roninson, I. B. (1986).Cell 47, 381–389.
Chou, P.-Y., and Fasman, G. D. (1978).Annu. Rev. Biochem. 47, 251–276.
Cohen, F. E., Abarbanel, R. M., Kuntz, I. D., and Fletterick, R. J. (1986).Biochemistry 25, 266–275.
Cheng, S. H., Rich, D. P., Marshall, J., Gregory, R. J., Welsh, M. J., and Smith, A. E. (1991).Cell 66, 1027–1036.
Dayhoff, M. O., Barker, W. C., and Hunt, L. T. (1983).Methods Enzymol. 91, 524–545.
Esposti, M. D., Crimi, M., and Venturoli, G. (1990).Eur. J. Biochem. 190, 207–219.
Fasman, G. D. (1989). InPrediction of Protein Structure and the Principles of Protein Conformation (G. D. Fasman, ed.), Plenum Press, New York, pp. 193–301.
Fasman, G. D., and Gilbert, W. A. (1990).Trends. Biochem. Sci. 15, 89–92.
Felmlee, T., Pellett, S., and Welch, R. A. (1985).J. Bacteriol. 163, 94–105.
Foote, S. J., Thompson, J. K., Cowman, A. F., and Kemp, D. J. (1989).Cell 57, 921–930.
Garnier, J., Osguthorpe, D. J., and Robson, B. (1978).J. Mol. Biol. 120, 97–120.
Glaser, P., Sakamoto, H., Bellalou, J., Ullmann, A., and Danchin, A. (1988).EMBO J. 7, 3997–4004.
Gregory, R. J., Cheng, S. H., Rich, D. P., Marshall, J., Paul, S., Hehir, K., Ostedgaard, L., Klinger, K. W., Welsh, M. J., and Smith, A. E. (1990).Nature 347, 382–386.
Gros, P., Croop, J., and Housman, D. (1986).Cell 47, 371–380.
Gros, P., Raymond, M., Bell, J., and Housman, D. (1988).Mol. Cell. Biol. 8, 2770–2778.
Hyde, S. C., Emsley, P., Hartshorn, M. J., Mimmack, M. M., Gileadi, U., Pearce, S. R., Gallagher, M. P., Gill, D. R., Hubbard, R. E., and Higgins, C. F. (1990).Nature 346, 362–365.
Jannig, F. (1990).Trends Biomed. Sci. 15, 93–95.
Kaback, H. R. (1989).Harvey Lect. 83, 77–105.
Kartner, N., Hanrahan, J. W., Jensen, T. M., Naismith, A. L., Sun, S., Ackerley, C. A., Reyes, E. F., Tsui, L-C., Rommens, J. M., Bear, C. E., and Riordan, J. R. (1991).Cell 64, 681–691.
Krupinski, J., Coussen, F., Bakalyar, H. A., Tang, W-J., Feinstein, P. G., Orth, K., Slaughter, C., Reed, R. R., and Gilman, A. G. (1989).Science 244, 1558–1564.
Kuchler, K., Sterne, R. E., and Thorner, J. (1989).EMBO J. 8, 3973–3984.
Kyte, J., and Doolittle, R. F. (1982).J. Mol. Biol. 157, 105–132.
Lim, V. I. (1974).J. Mol. Biol. 88, 857–894.
McGrath, J. P., and Varshavsky, A. (1989).Nature 340, 400–404.
Mellado, W., and Horwitz, S. B. (1987).Biochemistry 26, 6900–6904.
Mimura, C. S., Holbrook, S. R., and Ames, G. F-L. (1991).Proc. Natl. Acad. Sci. USA 88, 84–88.
Monaco, J. J., Cho, S., and Attaya, M. (1990).Science 250, 1723–1726.
Mueckler, M., Caruso, C., Baldwin, S. A., Panico, M., Blench, I., Morris, H. R., Allard, W. J., Lienhard, G. E., and Lodish, H. F. (1985).Science 229, 941–945.
Needleman, S. B., and Wunsch, C. D. (1970).J. Mol. Biol. 48, 443–453.
Nicoll, D. A., Longoni, S., and Philipson, K. D. (1990).Science 250, 562–565.
Quinton, P. M. (1990).FASEB J. 4, 2709–2717.
Raymond, M., Gros, P., Whiteway, M., and Thomas, D. Y. (1992).Science 256, 232–234.
Rich, D. P., Gregory, R. J., Anderson, M. P., Manavalan, P., Smith, A. E., and Welsh, M. J. (1991).Science 253, 205–207.
Riordan, J. R., Rommens, J. M., Kerem, B.-S., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J.-L., Drumm, M. L., Iannuzzi, M. C., Collins, F. S., and Tsui, L.-C. (1989).Science 245, 1066–1073.
Rommens, J. M., Iannuzzi, M. C., Kerem, B-S., Drumm, M. L., Melmer, G., Dean, M., Rozmahel, R., Cole, J. L., Kennedy, D., Hidaka, N., Zsiga, M., Buchwald, M., Riordan, J. R., Tsui, L.-C., and Collins, F. S. (1989).Science 245, 1059–1065.
Stanfield, S. W., Ielpi, L., O'Brochta, D., Helinski, D. R., and Ditta, G. S. (1988).J. Bacteriol. 170, 3523–3530.
Strathdee, C. A., and Lo, R. Y. C. (1989).J. Bacteriol. 171, 916–928.
Trowsdale, J., Hanson, I., Mockridge, I., Beck, S., Townsend, A., and Kelly, A. (1990).Nature 348, 741–743.
Valverde, M. A., Diaz, M., Sepulveda, F. V., Gill, D. R., Hyde, S. C., and Higgins, C. F. (1992).Nature 355, 830–833.
Wang, R., Seror, S. J., Blight, M., Pratt, J. M., Broome-Smith, J. K., and Holland, I. B. (1991).J. Mol. Biol. 217, 441–454.
Walker, J. E., Saraste, M., Runswick, M. J., and Gay, N. J. (1982).EMBO J. 1, 945–951.
Zhang, J.-T., and Ling, V. (1991).J. Biol. Chem. 266, 18,224–18,232.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Manavalan, P., Smith, A.E. & McPherson, J.M. Sequence and structural homology among membrane-associated domains of CFTR and certain transporter proteins. J Protein Chem 12, 279–290 (1993). https://doi.org/10.1007/BF01028190
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01028190