Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Plasma membrane phosphoinositide organization by protein electrostatics

Nature volume 438, pages 605–611 (2005)Cite this article

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2), which comprises only about 1% of the phospholipids in the cytoplasmic leaflet of the plasma membrane, is the source of three second messengers, activates many ion channels and enzymes, is involved in both endocytosis and exocytosis, anchors proteins to the membrane through several structured domains and has other roles. How can a single lipid in a fluid bilayer regulate so many distinct physiological processes? Spatial organization might be the key to this. Recent studies suggest that membrane proteins concentrate PIP2 and, in response to local increases in intracellular calcium concentration, release it to interact with other biologically important molecules.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Functions of PIP2.
Figure 2: MARCKS acts as a reversible source of PIP2 in the plasma membrane.
Figure 3: The effector domain of MARCKS is mainly extended when bound to either a membrane or calmodulin.
Figure 4: GAP43 might act as a reversible PIP2 sink in the axonal growth cones of neurons, where it is highly concentrated.
Figure 5: The electrostatic mechanism by which membrane-bound clusters of basic residues laterally sequester the multivalent (z=−4) acidic lipid PIP2.
Figure 6: Postulated reversible PIP2 sequestration by the NMDA and epidermal growth factor (EGF) receptors.

Similar content being viewed by others

References

  1. Berridge, M. J. & Irvine, R. F. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312, 315–321 (1984).

    ADS  CAS  PubMed  Google Scholar 

  2. Berridge, M. J. & Irvine, R. F. Inositol phosphates and cell signalling. Nature 341, 197–205 (1989).

    ADS  CAS  PubMed  Google Scholar 

  3. Rhee, S. G. Regulation of phosphoinositide-specific phospholipase C. Annu. Rev. Biochem. 70, 281–312 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Rebecchi, M. J. & Pentyala, S. N. Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol. Rev. 80, 1291–1335 (2000).

    CAS  PubMed  Google Scholar 

  5. Swann, K., Larman, M. G., Saunders, C. M. & Lai, F. A. The cytosolic sperm factor that triggers Ca2+ oscillations and egg activation in mammals is a novel phospholipase C: PLCQ. Reproduction 127, 431–439 (2004).

    CAS  PubMed  Google Scholar 

  6. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    ADS  CAS  PubMed  Google Scholar 

  7. Cho, W. & Stahelin, R. V. Membrane-protein interactions in cell signaling and membrane trafficking. Annu. Rev. Biophys. Biomol. Struct. 34, 119–151 (2005).

    CAS  PubMed  Google Scholar 

  8. DiNitto, J. P., Cronin, T. C. & Lambright, D. G. Membrane recognition and targeting by lipid-binding domains. Sci. STKE 2003, re16 (2003).

  9. Lemmon, M. A. Phosphoinositide recognition domains. Traffic 4, 201–213 (2003).

    CAS  PubMed  Google Scholar 

  10. Hurley, J. H. & Meyer, T. Subcellular targeting by membrane lipids. Curr. Opin. Cell Biol. 13, 146–152 (2001).

    CAS  PubMed  Google Scholar 

  11. Suh, B. C. & Hille, B. Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate. Curr. Opin. Neurobiol. 15, 370–378 (2005).

    CAS  PubMed  Google Scholar 

  12. Hilgemann, D. W. Oily barbarians breach ion channel gates. Science 304, 223–224 (2004).

    CAS  PubMed  Google Scholar 

  13. Honing, S. et al. Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2. Mol. Cell 18, 519–531 (2005).

    PubMed  Google Scholar 

  14. Wenk, M. R. & De Camilli, P. Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: insights from vesicle recycling in nerve terminals. Proc. Natl Acad. Sci. USA 101, 8262–8269 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Simonsen, A., Wurmser, A. E., Emr, S. D. & Stenmark, H. The role of phosphoinositides in membrane transport. Curr. Opin. Cell Biol. 13, 485–492 (2001).

    CAS  PubMed  Google Scholar 

  16. Botelho, R. J. et al. Localized biphasic changes in phosphatidylinositol-4,5-bisphosphate at sites of phagocytosis. J. Cell Biol. 151, 1353–1368 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Holz, R. W. et al. A pleckstrin homology domain specific for phosphatidylinositol 4, 5-bisphosphate (PtdIns-4,5-P2) and fused to green fluorescent protein identifies plasma membrane PtdIns-4,5-P2 as being important in exocytosis. J. Biol. Chem. 275, 17878–17885 (2000).

    CAS  PubMed  Google Scholar 

  18. Martin, T. F. PI(4,5)P2 regulation of surface membrane traffic. Curr. Opin. Cell Biol. 13, 493–499 (2001).

    CAS  PubMed  Google Scholar 

  19. Di Paolo, G. et al. Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature 431, 415–422 (2004).

    ADS  CAS  PubMed  Google Scholar 

  20. Janmey, P. A. & Lindberg, U. Cytoskeletal regulation: rich in lipids. Nature Rev. Mol. Cell Biol. 5, 658–666 (2004).

    CAS  Google Scholar 

  21. Papayannopoulos, V. et al. A polybasic motif allows N-WASP to act as a sensor of PIP2 density. Mol. Cell 17, 181–191 (2005).

    CAS  PubMed  Google Scholar 

  22. Raucher, D. et al. Phosphatidylinositol 4,5-bisphosphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion. Cell 100, 221–228 (2000).

    CAS  PubMed  Google Scholar 

  23. Sciorra, V. A. et al. Dual role for phosphoinositides in regulation of yeast and mammalian phospholipase D enzymes. J. Cell Biol. 159, 1039–1049 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hinchliffe, K. A., Ciruela, A. & Irvine, R. F. PIPkins, their substrates and their products: new functions for old enzymes. Biochim. Biophys. Acta 1436, 87–104 (1998).

    CAS  PubMed  Google Scholar 

  25. van Rheenen, J., Achame, E. M., Janssen, H., Calafat, J. & Jalink, K. PIP2 signaling in lipid domains: a critical re-evaluation. EMBO J. 24, 1664–1673 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Golub, T. & Caroni, P. PI(4,5)P2-dependent microdomain assemblies capture microtubules to promote and control leading edge motility. J. Cell Biol. 169, 151–165 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Berridge, M. J., Bootman, M. D. & Roderick, H. L. Calcium signalling: dynamics, homeostasis and remodelling. Nature Rev. Mol. Cell Biol. 4, 517–529 (2003).

    CAS  Google Scholar 

  28. Laux, T. et al. GAP43, MARCKS, and CAP23 modulate PI(4,5)P2 at plasmalemmal rafts, and regulate cell cortex actin dynamics through a common mechanism. J. Cell Biol. 149, 1455–1472 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Dunker, A. K. et al. Intrinsically disordered protein. J. Mol. Graph. Model. 19, 26–59 (2001).

    CAS  PubMed  Google Scholar 

  30. Uversky, V. N. What does it mean to be natively unfolded? Eur. J. Biochem. 269, 2–12 (2002).

    CAS  PubMed  Google Scholar 

  31. Aderem Aderem, A. The MARCKS brothers: a family of protein kinase C substrates. Cell 71, 713–716 (1992).

    PubMed  Google Scholar 

  32. Blackshear Blackshear, P. J. The MARCKS family of cellular protein kinase C substrates. J. Biol. Chem. 268, 1501–1504 (1993).

    PubMed  Google Scholar 

  33. McLaughlin, S. & Aderem, A. The myristoyl-electrostatic switch: a modulator of reversible protein-membrane interactions. Trends Biochem. Sci. 20, 272–276 (1995).

    CAS  PubMed  Google Scholar 

  34. Arbuzova, A., Schmitz, A. A. & Vergeres, G. Cross-talk unfolded: MARCKS proteins. Biochem. J. 362, 1–12 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Sundaram, M., Cook, H. W. & Byers, D. M. The MARCKS family of phospholipid binding proteins: regulation of phospholipase D and other cellular components. Biochem. Cell Biol. 82, 191–200 (2004).

    CAS  PubMed  Google Scholar 

  36. Taniguchi, H. & Manenti, S. Interaction of myristoylated alanine-rich protein kinase C substrate (MARCKS) with membrane phospholipids. J. Biol. Chem. 268, 9960–9963 (1993).

    CAS  PubMed  Google Scholar 

  37. Kim, J., Shishido, T., Jiang, X., Aderem, A. & McLaughlin, S. Phosphorylation, high ionic strength, and calmodulin reverse the binding of MARCKS to phospholipid vesicles. J. Biol. Chem. 269, 28214–28219 (1994).

    CAS  PubMed  Google Scholar 

  38. Rusu, L., Gambhir, A., McLaughlin, S. & Radler, J. Fluorescence correlation spectroscopy studies of peptide and protein binding to phospholipid vesicles. Biophys. J. 87, 1044–1053 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gambhir, A. et al. Electrostatic sequestration of PIP2 on phospholipid membranes by basic/aromatic regions of proteins. Biophys. J. 86, 2188–2207 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. Arbuzova, A., Murray, D. & McLaughlin, S. MARCKS, membranes, and calmodulin: kinetics of their interaction. Biochim. Biophys. Acta 1376, 369–379 (1998).

    CAS  PubMed  Google Scholar 

  41. Ohmori, S. et al. Importance of protein kinase C targeting for the phosphorylation of its substrate, myristoylated alanine-rich C-kinase substrate. J. Biol. Chem. 275, 26449–26457 (2000).

    CAS  PubMed  Google Scholar 

  42. Qin, Z. & Cafiso, D. S. Membrane structure of protein kinase C and calmodulin binding domain of myristoylated alanine rich C kinase substrate determined by site-directed spin labeling. Biochemistry 35, 2917–2925 (1996).

    CAS  PubMed  Google Scholar 

  43. Wang, J., Arbuzova, A., Hangyas-Mihalyne, G. & McLaughlin, S. The effector domain of myristoylated alanine-rich C kinase substrate binds strongly to phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 276, 5012–5019 (2001).

    CAS  PubMed  Google Scholar 

  44. Victor, K., Jacob, J. & Cafiso, D. S. Interactions controlling the membrane binding of basic protein domains: phenylalanine and the attachment of the myristoylated alanine-rich C-kinase substrate protein to interfaces. Biochemistry 38, 12527–12536 (1999).

    CAS  PubMed  Google Scholar 

  45. Zhang, W., Crocker, E., McLaughlin, S. & Smith, S. O. Binding of peptides with basic and aromatic residues to bilayer membranes: phenylalanine in the myristoylated alanine-rich C kinase substrate effector domain penetrates into the hydrophobic core of the bilayer. J. Biol. Chem. 278, 21459–21466 (2003).

    CAS  PubMed  Google Scholar 

  46. Ellena, J. F., Burnitz, M. C. & Cafiso, D. S. Location of the myristoylated alanine-rich C-kinase substrate (MARCKS) effector domain in negatively charged phospholipid bicelles. Biophys. J. 85, 2442–2448 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. White, S. H. & Wimley, W. C. Membrane protein folding and stability: physical principles. Annu. Rev. Biophys. Biomol. Struct. 28, 319–365 (1999).

    CAS  PubMed  Google Scholar 

  48. Clapperton, J. A., Martin, S. R., Smerdon, S. J., Gamblin, S. J. & Bayley, P. M. Structure of the complex of calmodulin with the target sequence of calmodulin-dependent protein kinase I: studies of the kinase activation mechanism. Biochemistry 41, 14669–14679 (2002).

    CAS  PubMed  Google Scholar 

  49. Porumb, T., Crivici, A., Blackshear, P. J. & Ikura, M. Calcium binding and conformational properties of calmodulin complexed with peptides derived from myristoylated alanine-rich C kinase substrate (MARCKS) and MARCKS-related protein (MRP). Eur. Biophys. J. 25, 239–247 (1997).

    CAS  PubMed  Google Scholar 

  50. Yamauchi, E., Nakatsu, T., Matsubara, M., Kato, H. & Taniguchi, H. Crystal structure of a MARCKS peptide containing the calmodulin-binding domain in complex with Ca2+-calmodulin. Nature Struct. Biol. 10, 226–231 (2003).

    CAS  PubMed  Google Scholar 

  51. Benowitz, L. I. & Routtenberg, A. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 20, 84–91 (1997).

    CAS  PubMed  Google Scholar 

  52. Liu, Y. C. & Storm, D. R. Regulation of free calmodulin levels by neuromodulin: neuron growth and regeneration. Trends Pharmacol. Sci. 11, 107–111 (1990).

    CAS  PubMed  Google Scholar 

  53. Liang, X., Lu, Y., Neubert, T. A. & Resh, M. D. Mass spectrometric analysis of GAP-43/neuromodulin reveals the presence of a variety of fatty acylated species. J. Biol. Chem. 277, 33032–33040 (2002).

    CAS  PubMed  Google Scholar 

  54. Skene, J. H. & Virag, I. Posttranslational membrane attachment and dynamic fatty acylation of a neuronal growth cone protein, GAP-43. J. Cell Biol. 108, 613–624 (1989).

    CAS  PubMed  Google Scholar 

  55. Persechini, A. & Stemmer, P. M. Calmodulin is a limiting factor in the cell. Trends Cardiovasc. Med. 12, 3–37 (2002).

    Google Scholar 

  56. Black, D. J., Tran, Q. K. & Persechini, A. Monitoring the total available calmodulin concentration in intact cells over the physiological range in free Ca2+. Cell Calcium 35, 415–425 (2004).

    CAS  PubMed  Google Scholar 

  57. Isotani, E. et al. Real-time evaluation of myosin light chain kinase activation in smooth muscle tissues from a transgenic calmodulin-biosensor mouse. Proc. Natl Acad. Sci. USA 101, 6279–6284 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang, J. et al. Lateral sequestration of phosphatidylinositol 4,5-bisphosphate by the basic effector domain of myristoylated alanine-rich C kinase substrate is due to nonspecific electrostatic interactions. J. Biol. Chem. 277, 34401–34412 (2002).

    CAS  PubMed  Google Scholar 

  59. Holthuis, J. C. & Levine, T. P. Lipid traffic: floppy drives and a superhighway. Nature Rev. Mol. Cell Biol. 6, 209–220 (2005).

    CAS  Google Scholar 

  60. McLaughlin, S., Wang, J., Gambhir, A. & Murray, D. PIP2 and proteins: interactions, organization, and information flow. Annu. Rev. Biophys. Biomol. Struct. 31, 151–175 (2002).

    CAS  PubMed  Google Scholar 

  61. McLaughlin, S. The electrostatic properties of membranes. Annu. Rev. Biophys. Biophys. Chem. 18, 113–136 (1989).

    CAS  PubMed  Google Scholar 

  62. Ben-Tal, N., Honig, B., Peitzsch, R. M., Denisov, G. & McLaughlin, S. Binding of small basic peptides to membranes containing acidic lipids: theoretical models and experimental results. Biophys. J. 71, 561–575 (1996).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  63. Murray, D., Arbuzova, A., Honig, B. & McLaughlin, S. The role of electrostatic and nonpolar interactions in the association of peripheral proteins with membranes. Curr. Top. Membr. 52, 271–302 (2002).

    Google Scholar 

  64. Wang, J., Gambhir, A., McLaughlin, S. & Murray, D. A computational model for the electrostatic sequestration of PI(4,5)P2 by membrane-adsorbed basic peptides. Biophys. J. 86, 1969–1986 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. McLaughlin, S., Smith, S. O., Hayman, M. J. & Murray, D. An electrostatic engine model for autoinhibition and activation of the epidermal growth factor receptor (EGFR/ErbB) family. J. Gen. Physiol. 126, 41–53 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Wollmuth, L. P. & Sobolevsky, A. I. Structure and gating of the glutamate receptor ion channel. Trends Neurosci. 27, 321–328 (2004).

    CAS  PubMed  Google Scholar 

  67. Ehlers, M. D., Zhang, S., Bernhadt, J. P. & Huganir, R. L. Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84, 745–755 (1996).

    CAS  PubMed  Google Scholar 

  68. Ferguson, K. M. Active and inactive conformations of the epidermal growth factor receptor. Biochem. Soc. Trans. 32, 742–745 (2004).

    CAS  PubMed  Google Scholar 

  69. Uyemura, T., Takagi, H., Yanagida, T. & Sako, Y. Single-molecule analysis of epidermal growth factor signaling that leads to ultrasensitive calcium response. Biophys. J. 88, 3720–3730 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. De Matteis, M. A. & Godi, A. PI-loting membrane traffic. Nature Cell Biol. 6, 487–492 (2004).

    CAS  PubMed  Google Scholar 

  71. Honda, A. et al. Phosphatidylinositol 4-phosphate 5-kinase 4 is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell 99, 521–532 (1999).

    CAS  PubMed  Google Scholar 

  72. Tall, E. G., Spector, I., Pentyala, S. N., Bitter, I. & Rebecchi, M. J. Dynamics of phosphatidylinositol 4,5-bisphosphate in actin-rich structures. Curr. Biol. 10, 743–746 (2000).

    CAS  PubMed  Google Scholar 

  73. Watt, S. A., Kular, G., Fleming, I. N., Downes, C. P. & Lucocq, J. M. Subcellular localization of phosphatidylinositol 4,5-bisphosphate using the pleckstrin homology domain of phospholipase C δ1. Biochem. J. 363, 657–666 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. van Rheenen, J. & Jalink, K. Agonist-induced PIP2 hydrolysis inhibits cortical actin dynamics: regulation at a global but not at a micrometer scale. Mol. Biol. Cell 13, 3257–3267 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Doughman, R. L., Firestone, A. J. & Anderson, R. A. Phosphatidylinositol phosphate kinases put PI4,5P2 in its place. J. Membr. Biol. 194, 77–89 (2003).

    CAS  PubMed  Google Scholar 

  76. Chakravarthy, B., Morley, P. & Whitfield, J. Ca2+-calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains. Trends Neurosci. 22, 12–16 (1999).

    CAS  PubMed  Google Scholar 

  77. Van Haastert, P. J. & Devreotes, P. N. Chemotaxis: signalling the way forward. Nature Rev. Mol. Cell Biol. 5, 626–634 (2004).

    CAS  Google Scholar 

  78. Singh, S. M. & Murray, D. Molecular modeling of the membrane targeting of phospholipase C pleckstrin homology domains. Protein Sci. 12, 1934–1953 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Gallagher, K. & Sharp, K. Electrostatic contributions to heat capacity changes of DNA-ligand binding. Biophys. J. 75, 769–776 (1998).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nicholls, A., Sharp, K. A. & Honig, B. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons. Proteins 11, 281–296 (1991).

    CAS  PubMed  Google Scholar 

  81. Hunter, T., Ling, N. & Cooper, J. A. Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane. Nature 311, 480–483 (1984).

    ADS  CAS  PubMed  Google Scholar 

  82. Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309, 418–425 (1984).

    ADS  CAS  PubMed  Google Scholar 

  83. Li, H., Ruano, M. J. & Villalobo, A. Endogenous calmodulin interacts with the epidermal growth factor receptor in living cells. FEBS Lett. 559, 175–180 (2004).

    CAS  PubMed  Google Scholar 

  84. Graff, J. M., Young, T. N., Johnson, J. D. & Blackshear, P. J. Phosphorylation-regulated calmodulin binding to a prominent cellular substrate for protein kinase C. J. Biol. Chem. 264, 21818–21823 (1989).

    CAS  PubMed  Google Scholar 

  85. Yamniuk, A. P. & Vogel, H. J. Calmodulin’s flexibility allows for promiscuity in its interactions with target proteins and peptides. Mol. Biotechnol. 27, 33–57 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NIH and Carol M. Baldwin Foundation (to S.M) and NSF (to D.M.).

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, Health Sciences Center, Stony Brook University, Stony Brook, 11794, New York, USA

    Stuart McLaughlin

  2. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Diana Murray

Authors
  1. Stuart McLaughlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Diana Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McLaughlin, S., Murray, D. Plasma membrane phosphoinositide organization by protein electrostatics. Nature 438, 605–611 (2005). https://doi.org/10.1038/nature04398

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04398

This article is cited by

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.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing