Abstract
One of the great challenges for molecular biologists is to learn how a protein sequence defines its three-dimensional structure. For many years, the problem was even more difficult for membrane proteins because so little was known about what they looked like. The situation has improved markedly in recent years, and we now know over 90 unique structures. Our enhanced view of the structure universe, combined with an increasingly quantitative understanding of fold determination, engenders optimism that a solution to the folding problem for membrane proteins can be achieved.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aichinger, I. in The Art of the Tale (ed. Halpern, D.) 9–17 (Penguin Books, New York, NY, 1956).
Henderson, R. & Unwin, P. N. Three-dimensional model of purple membrane obtained by electron microscopy. Nature 257, 28–32 (1975).
Lenard, J. & Singer, S. Protein conformation in cell membrane preparations as studied by optical rotatory dispersion and circular dichroism. Proc. Natl Acad. Sci. USA 56, 1828–1835 (1966).
Kyte, J. & Doolittle, R. F. A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132 (1982).
Bigelow, H. R., Petrey, D. S., Liu, J., Przybylski, D. & Rost, B. Predicting transmembrane beta-barrels in proteomes. Nucleic Acids Res. 32, 2566–2577 (2004).
White, S. H. The progress of membrane protein structure determination. Protein Sci. 13, 1948–1949 (2004).
Fu, D. et al. Structure of a glycerol-conducting channel and the basis for its selectivity. Science 290, 481–486 (2000).
Cuthbertson, J. M., Doyle, D. A. & Sansom, M. S. Transmembrane helix prediction: a comparative evaluation and analysis. Protein Eng. Des. Sel. 18, 295–308 (2005).
Yohannan, S., Faham, S., Yang, D., Whitelegge, J. P. & Bowie, J. U. The evolution of transmembrane helix kinks and the structural diversity of G protein-coupled receptors. Proc. Natl Acad. Sci. USA 101, 959–963 (2004).
Popot, J. & Engelman, D. Membrane protein folding and oligomerization: the two-stage model. Biochemistry 29, 4031–4037 (1990).
White, S. H. & von Heijne, G. The machinery of membrane protein assembly. Curr. Opin. Struct. Biol. 14, 397–404 (2004).
Goder, V., Junne, T. & Spiess, M. Sec61p contributes to signal sequence orientation according to the positive-inside rule. Mol. Biol. Cell 15, 1470–1478 (2004).
Anfinsen, C. B. Principles that govern the folding of protein chains. Science 181, 223–230 (1973).
Engelman, D. M. et al. Membrane protein folding: beyond the two stage model. FEBS Lett. 555, 122–125 (2003).
White, S. H. & Wimley, W. C. Membrane protein folding and stability: physical principles. Annu. Rev. Biophys. Biomol. Struct. 28, 319–365 (1999).
Tieleman, D. P., Sansom, M. S. & Berendsen, H. J. Alamethicin helices in a bilayer and in solution: molecular dynamics simulations. Biophys. J. 76, 40–49 (1999).
Wiener, M. C. & White, S. H. Structure of a fluid dioleoylphosphatidylcholine bilayer determined by joint refinement of X-ray and neutron diffraction data. III. Complete structure. Biophys J. 61, 437–447 (1992).
Wimley, W. C., Creamer, T. P. & White, S. H. Solvation energies of amino acid side chains and backbone in a family of host-guest pentapeptides. Biochemistry 35, 5109–5124 (1996).
Liu, L. P., Li, S. C., Goto, N. K. & Deber, C. M. Threshold hydrophobicity dictates helical conformations of peptides in membrane environments. Biopolymers 39, 465–470 (1996).
Hessa, T. et al. Recognition of transmembrane helices by the endoplasmic reticulum translocon. Nature 433, 377–381 (2005).
Wimley, W. C. & White, S. H. Experimentally determined hydrophobicity scale for proteins at membrane interfaces. Nature Struct. Biol. 3, 842–848 (1996).
Van den Berg, B. et al. X-ray structure of a protein-conducting channel. Nature 427, 36–44 (2004).
Rapoport, T. A., Goder, V., Heinrich, S. U. & Matlack, K. E. Membrane-protein integration and the role of the translocation channel. Trends Cell Biol. 14, 568–575 (2004).
von Heijne, G. The distribution of positively charged reisues in bacterial inner membrane protiens correlates with the transmembrane topology. EMBO J. 5, 3021–3027 (1986).
Heinrich, S. U., Mothes, W., Brunner, J. & Rapoport, T. A. The Sec61p complex mediates the integration of a membrane protein by allowing lipid partitioning of the transmembrane domain. Cell 102, 233–244 (2000).
Chamberlain, A. K., Lee, Y., Kim, S. & Bowie, J. U. Snorkeling preferences foster an amino acid composition bias in transmembrane helices. J. Mol. Biol. 339, 471–479 (2004).
Hessa, T., White, S. H. & von Heijne, G. Membrane insertion of a potassium-channel voltage sensor. Science 307, 1427 (2005).
Nagy, J. K., Lonzer, W. L. & Sanders, C. R. Kinetic study of folding and misfolding of diacylglycerol kinase in model membranes. Biochemistry 40, 8971–8980 (2001).
Zhang, W., Campbell, H. A., King, S. C. & Dowhan, W. Phospholipids as determinants of membrane protein topology: Phosphatidylethanolamine is required for the proper topological organization of the gamma-aminobutyric acid permease (GabP) of Escherichia coli. J. Biol. Chem. 280, 26032–26038 (2005).
Dill, K. A. & Chan, H. S. From Levinthal to pathways to funnels. Nature Struct. Biol. 4, 10–19 (1997).
Lu, H. & Booth, P. J. The final stages of folding of the membrane protein bacteriorhodopsin occur by kinetically indistinguishable parallel folding paths that are mediated by pH. J. Mol. Biol. 299, 233–243 (2000).
Bowie, J. Helix packing in membrane proteins. J. Mol. Biol. 272, 780–789 (1997).
Huschilt, J., Millman, B. & Davis, J. Orientation of alpha-helical peptides in a lipid bilayer. Biochim. Biophys. Acta 979, 139–141 (1989).
Chothia, C., Levitt, M. & Richardson, D. Helix to helix packing in proteins. J. Mol. Biol. 145, 215–250 (1981).
Langosch, D. & Heringa, J. Interaction of transmembrane helices by a knobs-into-holes packing characteristic of soluble coiled coils. Proteins 31, 150–159 (1998).
Jiang, S. & Vakser, I. A. Side chains in transmembrane helices are shorter at helix–helix interfaces. Proteins 40, 429–435 (2000).
Curran, A. R. & Engelman, D. M. Sequence motifs, polar interactions and conformational changes in helical membrane proteins. Curr. Opin. Struct. Biol. 13, 412–417 (2003).
Jiang, S. & Vakser, I. A. Shorter side chains optimize helix-helix packing. Protein Sci. 13, 1426–1429 (2004).
MacKenzie, K. & Engelman, D. Structure-based prediction of the stability of transmembrane helix-helix interactions: the sequence dependence of glycophorin A dimerization. Proc. Natl Acad. Sci. USA 95, 3583–3590 (1998).
Senes, A., Ubarretxena-Belandia, I. & Engelman, D. M. The Cα–H.O hydrogen bond: a determinant of stability and specificity in transmembrane helix interactions. Proc. Natl Acad. Sci. USA 98, 9056–9061 (2001).
Arbely, E. & Arkin, I. T. Experimental measurement of the strength of a Calpha-H.O bond in a lipid bilayer. J. Am. Chem. Soc. 126, 5362–5363 (2004).
Fleishman, S. J. & Ben-Tal, N. A novel scoring function for predicting the conformations of tightly packed pairs of transmembrane alpha-helices. J. Mol. Biol. 321, 363–378 (2002).
Riek, R. P., Rigoutsos, I., Novotny, J. & Graham, R. M. Non-alpha-helical elements modulate polytopic membrane protein architecture. J. Mol. Biol. 306, 349–362 (2001).
Cordes, F. S., Bright, J. N. & Sansom, M. S. Proline-induced distortions of transmembrane helices. J. Mol. Biol. 323, 951–960 (2002).
Rigoutsos, I., Riek, P., Graham, R. M. & Novotny, J. Structural details (kinks and non-alpha conformations) in transmembrane helices are intrahelically determined and can be predicted by sequence pattern descriptors. Nucleic Acids Res. 31, 4625–4631 (2003).
Deupi, X. et al. Ser and Thr residues modulate the conformation of pro-kinked transmembrane alpha-helices. Biophys. J. 86, 105–115 (2004).
Wigley, W. C. et al. A protein sequence that can encode native structure by disfavoring alternate conformations. Nature Struct. Biol. 9, 381–388 (2002).
Fleming, K. G. & Engelman, D. M. Computation and mutagenesis suggest a right-handed structure for the synaptobrevin transmembrane dimer. Proteins 45, 313–317 (2001).
Faham, S. et al. Side-chain contributions to membrane protein structure and stability. J. Mol. Biol. 335, 297–305 (2004).
Eilers, M., Patel, A. B., Liu, W. & Smith, S. O. Comparison of helix interactions in membrane and soluble alpha-bundle proteins. Biophys. J. 82, 2720–2736 (2002).
Eilers, M., Shekar, S. C., Shieh, T., Smith, S. O. & Fleming, P. J. Internal packing of helical membrane proteins. Proc. Natl Acad. Sci. USA 97, 5796–5801 (2000).
Hildebrand, P. W., Rother, K., Goede, A., Preissner, R. & Frommel, C. Molecular packing and packing defects in helical membrane proteins. Biophys. J. 88, 1970–1977 (2005).
Adamian, L. & Liang, J. Helix-helix packing and interfacial pairwise interactions of residues in membrane proteins. J. Mol. Biol. 311, 891–907 (2001).
Richards, F. M. The interpretation of protein structures: total volume, group volume distributions and packing density. J. Mol. Biol. 82, 1–14 (1974).
Marrink, S., Sok, R. & Berendsen, H. J. Free volume properties of a simulated lipid membrane. J. Chem. Phys. 104, 9090–9099 (1996).
Rees, D., DeAntonio, L. & Eisenberg, D. Hydrophobic organization of membrane proteins. Science 245, 510–513 (1989).
Adamian, L. & Liang, J. Interhelical hydrogen bonds and spatial motifs in membrane proteins: polar clamps and serine zippers. Proteins 47, 209–218 (2002).
Chamberlain, A. K., Faham, S., Yohannan, S. & Bowie, J. U. Construction of helix-bundle membrane proteins. Adv. Protein Chem. 63, 19–46 (2003).
Lear, J. D., Gratkowski, H., Adamian, L., Liang, J. & DeGrado, W. F. Position-dependence of stabilizing polar interactions of asparagine in transmembrane helical bundles. Biochemistry 42, 6400–6407 (2003).
Zhou, F. X., Merianos, H. J., Brunger, A. T. & Engelman, D. M. Polar residues drive association of polyleucine transmembrane helices. Proc. Natl Acad. Sci. USA 98, 2250–2255 (2001).
Choma, C., Gratkowski, H., Lear, J. D. & DeGrado, W. F. Asparagine-mediated self-association of a model transmembrane helix. Nature Struct. Biol. 7, 161–166 (2000).
Li, R. et al. Activation of integrin αIIbβ3 by modulation of transmembrane helix associations. Science 300, 795–798 (2003).
Gratkowski, H., Lear, J. D. & DeGrado, W. F. Polar side chains drive the association of model transmembrane peptides. Proc. Natl Acad. Sci. USA 98, 880–885 (2001).
Zhou, F. X., Cocco, M. J., Russ, W. P., Brunger, A. T. & Engelman, D. M. Interhelical hydrogen bonding drives strong interactions in membrane proteins. Nature Struct. Biol. 7, 154–160 (2000).
Partridge, A. W., Therien, A. G. & Deber, C. M. Missense mutations in transmembrane domains of proteins: phenotypic propensity of polar residues for human disease. Proteins 54, 648–656 (2004).
Smith, S., Smith, C. & Bormann, B. Strong hydrogen bonding interactions involving a buried glutamic acid in the transmembrane sequence of the neu/erbB-2 receptor. Nature Struct. Biol. 3, 252–258 (1996).
Weiner, D., Liu, J., Cohen, J., Williams, W. V. & Green, M. A point mutation in the neu oncogene mimics ligand induction of receptor aggregation. Nature 339, 230–231 (1989).
Therien, A. G., Grant, F. E. & Deber, C. M. Interhelical hydrogen bonds in the CFTR membrane domain. Nature Struct. Biol. 8, 597–601 (2001).
Vargas, R., Garza, J., Dixon, D. A. & Hay, B. P. How strong is the Cα–H···O=C hydrogen bond? J. Am. Chem. Soc. 122, 4750–4755 (2000).
Yohannan, S. et al. A Cα-H.O hydrogen bond in a membrane protein is not stabilizing. J. Am. Chem. Soc. 126, 2284–2285 (2004).
Mottamal, M. & Lazaridis, T. The contribution of Cα-H.O hydrogen bonds to membrane protein stability depends on the position of the amide. Biochemistry 44, 1607–1613 (2005).
Lee, A. G. How lipids affect the activities of integral membrane proteins. Biochim. Biophys. Acta 1666, 62–87 (2004).
Gruner, S. M. Intrinsic curvature hypothesis for biomembrane lipid composition: a role for nonbilayer lipids. Proc. Natl Acad. Sci. USA 82, 3665–3669 (1985).
Hong, H. & Tamm, L. K. Elastic coupling of integral membrane protein stability to lipid bilayer forces. Proc. Natl Acad. Sci. USA 101, 4065–4070 (2004).
Allen, S. J., Curran, A. R., Templer, R. H., Meijberg, W. & Booth, P. J. Controlling the folding efficiency of an integral membrane protein. J. Mol. Biol. 342, 1293–1304 (2004).
O'Keeffe, A. H., East, J. M. & Lee, A. G. Selectivity in lipid binding to the bacterial outer membrane protein OmpF. Biophys. J. 79, 2066–2074 (2000).
Williamson, I. M., Alvis, S. J., East, J. M. & Lee, A. G. Interactions of phospholipids with the potassium channel KcsA. Biophys. J. 83, 2026–2038 (2002).
Powl, A. M., East, J. M. & Lee, A. G. Lipid-protein interactions studied by introduction of a tryptophan residue: the mechanosensitive channel MscL. Biochemistry 42, 14306–14317 (2003).
Mitra, K., Ubarretxena-Belandia, I., Taguchi, T., Warren, G. & Engelman, D. M. Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol. Proc. Natl Acad. Sci. USA 101, 4083–4088 (2004).
Abramovitch, D. A., Marsh, D. & Powell, G. L. Activation of beef-heart cytochrome c oxidase by cardiolipin and analogues of cardiolipin. Biochim. Biophys. Acta 1020, 34–42 (1990).
Valiyaveetil, F. I., Zhou, Y. & MacKinnon, R. Lipids in the structure, folding, and function of the KcsA K+ channel. Biochemistry 41, 10771–10777 (2002).
Schonbrun, J., Wedemeyer, W. J. & Baker, D. Protein structure prediction in 2002. Curr. Opin. Struct. Biol. 12, 348–354 (2002).
Briggs, J. A., Torres, J. & Arkin, I. T. A new method to model membrane protein structure based on silent amino acid substitutions. Proteins 44, 370–375 (2001).
Kim, S., Chamberlain, A. K. & Bowie, J. U. Membrane channel structure of Helicobacter pylori vacuolating toxin: role of multiple GXXXG motifs in cylindrical channels. Proc. Natl Acad. Sci. USA 101, 5988–5991 (2004).
Sale, K., Faulon, J. L., Gray, G. A., Schoeniger, J. S. & Young, M. M. Optimal bundling of transmembrane helices using sparse distance constraints. Protein Sci. 13, 2613–2627 (2004).
Adams, P., Engelman, D. & Brünger, A. Improved prediction fo the structure of the dimeric transmembrane domain of glycophorin A obtained through global searching. Proteins Struct. Func. Genet. 26, 257–261 (1996).
Fleishman, S. J., Unger, V. M., Yeager, M. & Ben-Tal, N. A Cα model for the transmembrane alpha helices of gap junction intercellular channels. Mol. Cell 15, 879–888 (2004).
White, S. H. & Wimley, W. C. Hydrophobic interactions of peptides with membrane interfaces. Biochim. Biophys. Acta 1376, 339–352. (1998).
MacKenzie, K., Prestegard, J. & Engelman, D. A transmembrane helix dimer: structure and implications. Science 276, 131–133 (1997).
Acknowledgements
I would like to thank members of my lab for helpful comments and NIH for support. J.U.B. is a Leukemia and Lymphoma Society Scholar.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Additional information
Author Information Reprints and permissions is available at npg.nature.com/reprintsand permissions.
Rights and permissions
About this article
Cite this article
Bowie, J. Solving the membrane protein folding problem. Nature 438, 581–589 (2005). https://doi.org/10.1038/nature04395
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature04395
This article is cited by
-
Evolutionary balance between foldability and functionality of a glucose transporter
Nature Chemical Biology (2022)
-
Complete genome of the thermophilic purple sulfur Bacterium Thermochromatium tepidum compared to Allochromatium vinosum and other Chromatiaceae
Photosynthesis Research (2022)
-
Towards a Quantitative Understanding of Protein–Lipid Bilayer Interactions at the Single Molecule Level: Opportunities and Challenges
The Journal of Membrane Biology (2021)
-
Triacylglycerols sequester monotopic membrane proteins to lipid droplets
Nature Communications (2020)
-
Functionality of membrane proteins overexpressed and purified from E. coli is highly dependent upon the strain
Scientific Reports (2019)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.