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Emerging roles for lipids in shaping membrane-protein function

Nature volume 459, pages 379–385 (2009)Cite this article

Abstract

Studies of membrane proteins have revealed a direct link between the lipid environment and the structure and function of some of these proteins. Although some of these effects involve specific chemical interactions between lipids and protein residues, many can be understood in terms of protein-induced perturbations to the membrane shape. The free-energy cost of such perturbations can be estimated quantitatively, and measurements of channel gating in model systems of membrane proteins with their lipid partners are now confirming predictions of simple models.

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Figure 1: Ion-channel function and membrane properties.
Figure 2: Geometry, deformations and energies of dilute and crowded membranes.
Figure 3: Structure and energy at the protein–lipid interface.
Figure 4: Membrane-protein interactions and conformational state.

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References

  1. Engelman, D. M. Membranes are more mosaic than fluid. Nature 438, 578–580 (2005).

    Article  ADS  CAS  Google Scholar 

  2. Sukharev, S. I. et al. Energetic and spatial parameters for gating of the bacterial large conductance mechanosensitive channel, MscL. J. Gen. Physiol. 113, 525–540 (1999).

    Article  CAS  Google Scholar 

  3. Perozo, E. et al. Physical principles underlying the transduction of bilayer deformation forces during mechanosensitive channel gating. Nature Struct. Biol. 9, 696–703 (2002). This paper describes experiments that show how the gating behaviour of mechanosensitive channels depends on the acyl chain lengths of the lipids around them.

    Article  CAS  Google Scholar 

  4. Andersen, O.S. & Koeppe, R.E. II Bilayer thickness and membrane protein function: an energetic perspective. Annu. Rev. Biophys. Biomol. Struct. 36, 107–130 (2007). This useful review provides a variety of examples of the connection between the lipid environment and the function of membrane-bound proteins.

    Article  CAS  Google Scholar 

  5. Marsh, D. Protein modulation of lipids, and vice-versa, in membranes. Biochim. Biophys. Acta 1778, 1545–1575 (2008).

    Article  CAS  Google Scholar 

  6. Killian, J. A. Hydrophobic mismatch between proteins and lipids in membranes. Biochim. Biophys. Acta 1376, 401–415 (1998).

    Article  CAS  Google Scholar 

  7. Petsko, G. & Ringe, D. Protein Structure and Function (New Science Press, 2004).

    Google Scholar 

  8. Moe, P. & Blount, P. Assessment of potential stimuli for mechano-dependent gating of MscL: effects of pressure, tension, and lipid headgroups. Biochemistry 44, 12239–12244 (2005).

    Article  CAS  Google Scholar 

  9. Lee, A. G. How lipids affect the activities of integral membrane proteins. Biochim. Biophys. Acta 1666, 62–87 (2004). This review discusses how specific residues in the structure of transmembrane proteins determine hydrophobic thickness and addresses the topic of site-specific lipid binding.

    Article  CAS  Google Scholar 

  10. Valiyaveetil, F. I., Zhou, Y. & MacKinnon, R. Lipids in the structure, folding, and function of the KcsA K+ channel. Biochemistry 41, 10771–10777 (2002).

    Article  CAS  Google Scholar 

  11. Lundbaek, J. A. et al. Capsaicin regulates voltage-dependent sodium channels by altering lipid bilayer elasticity. Mol. Pharmacol. 68, 680–689 (2005).

    CAS  PubMed  Google Scholar 

  12. Suchyna, T. M. et al. Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature 430, 235–240 (2004).

    Article  ADS  CAS  Google Scholar 

  13. Jensen, M. O. & Mouritsen, O. G. Lipids do influence protein function — the hydrophobic matching hypothesis revisited. Biochim. Biophys. Acta 1666, 205–226 (2004). This review discusses the qualitative effects of thickness mismatch on membrane proteins and summarizes evidence of the effects of bilayer thickness on enzymatic activity.

    Article  CAS  Google Scholar 

  14. Goulian, M. et al. Gramicidin channel kinetics under tension. Biophys. J. 74, 328–337 (1998).

    Article  ADS  CAS  Google Scholar 

  15. Schmidt, D. & MacKinnon, R. Voltage-dependent K+ channel gating and voltage sensor toxin sensitivity depend on the mechanical state of the lipid membrane. Proc. Natl Acad. Sci. USA 105, 19276–19281 (2008).

    Article  ADS  CAS  Google Scholar 

  16. Calabrese, B. et al. Mechanosensitivity of N-type calcium channel currents. Biophys. J. 83, 2560–2574 (2002).

    Article  ADS  CAS  Google Scholar 

  17. Morris, C. E. & Juranka, P. F. Nav channel mechanosensitivity: activation and inactivation accelerate reversibly with stretch. Biophys. J. 93, 822–833 (2007).

    Article  ADS  CAS  Google Scholar 

  18. Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006). This paper provides an experimental treatment of the crowded nature of biological membranes.

    Article  CAS  Google Scholar 

  19. Dupuy, A. D. & Engelman, D. M. Protein area occupancy at the center of the red blood cell membrane. Proc. Natl Acad. Sci. USA 105, 2848–2852 (2008).

    Article  ADS  CAS  Google Scholar 

  20. Mitra, K. et al. Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol. Proc. Natl Acad. Sci. USA 101, 4083–4088 (2004). This experimental tour de force shows that protein content modulates bilayer thickness across different organellar membranes by the hydrophobic mismatch principle.

    Article  ADS  CAS  Google Scholar 

  21. Zimmerman, S. B. & Minton, A. P. Macromolecular crowding: biochemical, biophysical, and physiological consequences. Annu. Rev. Biophys. Biomol. Struct. 22, 27–65 (1993).

    Article  CAS  Google Scholar 

  22. Ellis, R. J. Macromolecular crowding: obvious but underappreciated. Trends Biochem. Sci. 26, 597–604 (2001).

    Article  CAS  Google Scholar 

  23. Bond, P. J. & Sansom, M. S. Bilayer deformation by the Kv channel voltage sensor domain revealed by self-assembly simulations. Proc. Natl Acad. Sci. USA 104, 2631–2636 (2007).

    Article  ADS  CAS  Google Scholar 

  24. Chen, X. et al. Gating mechanisms of mechanosensitive channels of large conductance, I: a continuum mechanics-based hierarchical framework. Biophys. J. 95, 563–580 (2008).

    Article  ADS  CAS  Google Scholar 

  25. Elmore, D. E. & Dougherty, D. A. Investigating lipid composition effects on the mechanosensitive channel of large conductance (MscL) using molecular dynamics simulations. Biophys. J. 85, 1512–1524 (2003).

    Article  CAS  Google Scholar 

  26. Jeon, J. & Voth, G. A. Gating of the mechanosensitive channel protein MscL: the interplay of membrane and protein. Biophys. J. 94, 3497–3511 (2008).

    Article  ADS  CAS  Google Scholar 

  27. Marsh, D. Lateral pressure profile, spontaneous curvature frustration, and the incorporation and conformation of proteins in membranes. Biophys. J. 93, 3884–3899 (2007).

    Article  ADS  CAS  Google Scholar 

  28. Cantor, R. The influence of membrane lateral pressures on simple geometric models of protein conformational equilibria. Chem. Phys. Lipids 101, 45–56 (1999).

    Article  CAS  Google Scholar 

  29. Marsh, D. Elastic curvature constants of lipid monolayers and bilayers. Chem. Phys. Lipids 144, 146–159 (2006). This review compiles measurements of membrane elastic properties across different lipid types and builds scaling laws that connect different modes of bilayer deformation to bulk bilayer properties.

    Article  CAS  Google Scholar 

  30. Dan, N., Pincus, P. & Safran, S. Membrane-induced interactions between inclusions. Langmuir 9, 2768–2771 (1993).

    Article  CAS  Google Scholar 

  31. Markin, V. S. & Sachs, F. Thermodynamics of mechanosensitivity. Phys. Biol. 1, 110–124 (2004).

    Article  ADS  CAS  Google Scholar 

  32. Mouritsen, O. G. & Bloom, M. Models of lipid-protein interactions in membranes. Annu. Rev. Biophys. Biomol. Struct. 22, 145–171 (1993).

    Article  CAS  Google Scholar 

  33. Boal, D. Mechanics of the Cell (Cambridge University Press, 2002).

    Google Scholar 

  34. Gruner, S. M. Intrinsic curvature hypothesis for biomembrane lipid composition: a role for nonbilayer lipids. Proc. Natl Acad. Sci. USA 82, 3665–3669 (1985).

    Article  ADS  CAS  Google Scholar 

  35. Mouritsen, O. G. & Bloom, M. Mattress model of lipid–protein interactions in membranes. Biophys. J. 46, 141–153 (1984).

    Article  CAS  Google Scholar 

  36. Huang, H. W., Deformation free energy of bilayer membrane and its effect on gramicidin channel lifetime. Biophys. J. 50, 1061–1070 (1986).

    Article  ADS  CAS  Google Scholar 

  37. Turner, M. S. & Sens, P. Gating-by-tilt of mechanically sensitive membrane channels. Phys. Rev. Lett. 93, 118103 (2004).

    Article  ADS  Google Scholar 

  38. Wiggins, P. & Phillips, R. Membrane-protein interactions in mechanosensitive channels. Biophys. J. 88, 880–902 (2005).

    Article  ADS  CAS  Google Scholar 

  39. Turner, M. S. & Sens, P. Inclusions on fluid membranes anchored to elastic media. Biophys. J. 76, 564–572 (1999).

    Article  ADS  CAS  Google Scholar 

  40. Wiggins, P. & Phillips, R. Analytic models for mechanotransduction: gating a mechanosensitive channel. Proc. Natl Acad. Sci. USA 101, 4071–4076 (2004).

    Article  ADS  CAS  Google Scholar 

  41. Dan, N. & Safran, S. A. Effect of lipid characteristics on the structure of transmembrane proteins. Biophys. J. 75, 1410–1414 (1998).

    Article  ADS  CAS  Google Scholar 

  42. Nielsen, C., Goulian, M. & Andersen, O. S. Energetics of inclusion-induced bilayer deformations. Biophys. J. 74, 1966–1983 (1998).

    Article  ADS  CAS  Google Scholar 

  43. Ursell, T., Reeves, D., Wiggins, P. & Phillips, R. in Mechanosensitive Ion Channels (ed. Kamkin, A. & Kisileva, I.) 37–70 (Springer, 2008).

    Book  Google Scholar 

  44. Cantor, R. S. Lateral pressures in cell membranes: A mechanism for modulation of protein function. J. Phys. Chem. B 101, 1723–1725 (1997).

    Article  CAS  Google Scholar 

  45. Bruinsma, R., Goulian, M. & Pincus, P. Self-assembly of membrane junctions. Biophys. J. 67, 746–750 (1994).

    Article  ADS  CAS  Google Scholar 

  46. Gil, T. et al. Theoretical analysis of protein organization in lipid membranes. Biochim. Biophys. Acta 1376, 245–266 (1998).

    Article  CAS  Google Scholar 

  47. Muller, M. M., Deserno, M. & Guven, J. Interface-mediated interactions between particles: a geometrical approach. Phys. Rev. E 72, 061407 (2005).

    Article  ADS  MathSciNet  Google Scholar 

  48. Reynwar, B. J. et al. Aggregation and vesiculation of membrane proteins by curvature-mediated interactions. Nature 447, 461–464 (2007).

    Article  ADS  CAS  Google Scholar 

  49. Golestanian, R., Goulian, M. & Kardar, M. Fluctuation-induced interactions between rods on a membrane. Phys. Rev. E 54, 6725–6734 (1996).

    Article  ADS  CAS  Google Scholar 

  50. Goulian, M., Bruinsma, R. & Pincus, P. Long-range forces in heterogeneous fluid membranes. Europhys. Lett. 22, 145–150 (1993).

    Article  CAS  Google Scholar 

  51. Sheetz, M.P., Sable, J.E. & Dobereiner, H. G. Continuous membrane-cytoskeleton adhesion requires continuous accommodation to lipid and cytoskeleton dynamics. Annu. Rev. Biophys. Biomol. Struct. 35, 417–434 (2006).

    Article  CAS  Google Scholar 

  52. Weikl, T. R., Kozlov, M. M. & Helfrich, W. Interaction of conical membrane inclusions: Effect of lateral tension. Phys. Rev. E 57, 6988–6995 (1998).

    Article  ADS  CAS  Google Scholar 

  53. Goforth, R. L. et al. Hydrophobic coupling of lipid bilayer energetics to channel function. J. Gen. Physiol. 121, 477–493 (2003).

    Article  CAS  Google Scholar 

  54. Sens, P., Johannes, L. & Bassereau, P. Biophysical approaches to protein-induced membrane deformations in trafficking. Curr. Opin. Cell Biol. 20, 476–482 (2008).

    Article  CAS  Google Scholar 

  55. Blood, P. D. & Voth, G. A. Direct observation of Bin/amphiphysin/Rvs (BAR) domain-induced membrane curvature by means of molecular dynamics simulations. Proc. Natl Acad. Sci. USA 103, 15068–15072 (2006).

    Article  ADS  CAS  Google Scholar 

  56. Reynwar, B. J. et al. Aggregation and vesiculation of membrane proteins by curvature-mediated interactions. Nature 447, 461–464 (2007).

    Article  ADS  CAS  Google Scholar 

  57. Arkhipov, A., Yin, Y. & Schulten, K. Four-scale description of membrane sculpting by BAR domains. Biophys. J. 95, 2806–2821 (2008).

    Article  ADS  CAS  Google Scholar 

  58. Kim, K. S., Neu, J. & Oster, G. Curvature-mediated interactions between membrane proteins. Biophys. J. 75, 2274–2291 (1998).

    Article  CAS  Google Scholar 

  59. Leibler, S. Curvature instability in membranes. J. Physique 47, 507–516 (1986).

    Article  CAS  Google Scholar 

  60. Sens, P. & Turner, M. S. Theoretical model for the formation of caveolae and similar membrane invaginations. Biophys. J. 86, 2049–2057 (2004).

    Article  ADS  CAS  Google Scholar 

  61. Ursell, T. et al. Cooperative gating and spatial organization of membrane proteins through elastic interactions. PLoS Comput. Biol. 3, e81 (2007).

    Article  ADS  Google Scholar 

  62. Zhou, H. X., Rivas, G. & Minton, A. P. Macromolecular crowding and confinement: biochemical, biophysical, and potential physiological consequences. Annu. Rev. Biophys. 37, 375–397 (2008).

    Article  CAS  Google Scholar 

  63. Chang, G. et al. Structure of the MscL homolog from Mycobacterium tuberculosis: a gated mechanosensitive ion channel. Science 282, 2220–2226 (1998).

    Article  ADS  CAS  Google Scholar 

  64. Bass, R. B. et al. Crystal structure of Escherichia coli MSCS, a voltage-modulated and mechanosensitive channel. Science 298, 1582–1587 (2002).

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

We are grateful to many people for insights and comments. In particular, we thank O. Andersen, M. Bialecka, F. Brown, N. Dan, L. Haswell, S. Johnson, J. Kondev, R. MacKinnon, C. Morris, D. Rees, D. Reeves, F. Sachs, D. Schmidt, S. Scheuring, S. Sukharev, M. Turner, S. White and M. Widom. We are also grateful to several anonymous reviewers for insightful comments. In addition, we are grateful to the US National Science Foundation and the National Institutes of Health for support through NIH Award number R01 GM084211 and the Director's Pioneer Award. The reference list for this article was constrained by length limits, and as a result the references cited here are representative rather than comprehensive. We apologize to those whose references are not cited as a result of either space limitations or our ignorance.

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Authors and Affiliations

  1. Department of Applied Physics, California Institute of Technology, Pasadena, 91125, California, USA

    Rob Phillips & Tristan Ursell

  2. Whitehead Institute of Biomedical Research, Cambridge, 02142, Massachusetts, USA

    Paul Wiggins

  3. UMR Gulliver CNRS-ESPCI, Paris, 7083, France

    Pierre Sens

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Correspondence should be addressed to R.P. (phillips@pboc.caltech.edu).

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Phillips, R., Ursell, T., Wiggins, P. et al. Emerging roles for lipids in shaping membrane-protein function. Nature 459, 379–385 (2009). https://doi.org/10.1038/nature08147

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