Membrane curvature enables N-Ras lipid anchor sorting to liquid-ordered membrane phases

Abstract

Trafficking and sorting of membrane-anchored Ras GTPases are regulated by partitioning between distinct membrane domains. Here, in vitro experiments and microscopic molecular theory reveal membrane curvature as a new modulator of N-Ras lipid anchor and palmitoyl chain partitioning. Membrane curvature was essential for enrichment in raft-like liquid-ordered phases; enrichment was driven by relief of lateral pressure upon anchor insertion and most likely affects the localization of lipidated proteins in general.

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Figure 1: Membrane curvature enables the association of tN-Ras and palmitoyl anchors with lo membrane phases.
Figure 2: Increased relief of the lateral pressure in curved lo versus ld membranes as the underlying mechanism for preferential lo partitioning of lipidated moieties in highly curved membranes.

References

  1. 1

    Cox, A.D. & Der, C. Small GTPases 1, 2–27 (2010).

    Article  Google Scholar 

  2. 2

    Hancock, J.F. Nat. Rev. Mol. Cell Biol. 4, 373–384 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Belanis, L., Plowman, S.J., Rotblat, B., Hancock, J.F. & Kloog, Y. Mol. Biol. Cell 19, 1404–1414 (2008).

    CAS  Article  Google Scholar 

  4. 4

    Hancock, J.F. & Parton, R.G. Biochem. J. 389, 1–11 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Prior, I.A. et al. Nat. Cell Biol. 3, 368–375 (2001).

    CAS  Article  Google Scholar 

  6. 6

    Yan, J., Roy, S., Apolloni, A., Lane, A. & Hancock, J.F. J. Biol. Chem. 273, 24052–24056 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Weise, K., Triola, G., Brunsveld, L., Waldmann, H. & Winter, R. J. Am. Chem. Soc. 131, 1557–1564 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Johnson, S.A. et al. Biochim. Biophys. Acta 1798, 1427–1435 (2010).

    CAS  Article  Google Scholar 

  9. 9

    Nicolini, C. et al. J. Am. Chem. Soc. 128, 192–201 (2006).

    CAS  Article  Google Scholar 

  10. 10

    Simons, K. & Gerl, M.J. Nat. Rev. Mol. Cell Biol. 11, 688–699 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Anderson, R.G.W. Annu. Rev. Biochem. 67, 199–225 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Kunding, A.H., Mortensen, M.W., Christensen, S.M. & Stamou, D. Biophys. J. 95, 1176–1188 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Bendix, P.M., Pedersen, M.S. & Stamou, D. Proc. Natl. Acad. Sci. USA 106, 12341–12346 (2009).

    CAS  Article  Google Scholar 

  14. 14

    Hatzakis, N.S. et al. Nat. Chem. Biol. 5, 835–841 (2009).

    CAS  Article  Google Scholar 

  15. 15

    Kamal, M.M., Mills, D., Grzybek, M. & Howard, J. Proc. Natl. Acad. Sci. USA 106, 22245–22250 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Roux, A. et al. EMBO J. 24, 1537–1545 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Vamparys, L. et al. Biophys. J. 104, 585–593 (2013).

    CAS  Article  Google Scholar 

  18. 18

    Meinhardt, S., Vink, R.L.C. & Schmid, F. Proc. Natl. Acad. Sci. USA 110, 4476–4481 (2013).

    CAS  Article  Google Scholar 

  19. 19

    Cui, H., Lyman, E. & Voth, G.A. Biophys. J. 100, 1271–1279 (2011).

    CAS  Article  Google Scholar 

  20. 20

    Uline, M.J., Longo, G.S., Schick, M. & Szleifer, I. Biophys. J. 98, 1883–1892 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Sampaio, J.L., Moreno, M.J. & Vaz, W.L.C. Biophys. J. 88, 4064–4071 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Abreu, M.S.C., Moreno, M.J. & Vaz, W.L.C. Biophys. J. 87, 353–365 (2004).

    CAS  Article  Google Scholar 

  23. 23

    Sezgin, E. et al. Biochim. Biophys. Acta 1818, 1777–1784 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Parthasarathy, R., Yu, C.H. & Groves, J.T. Langmuir 22, 5095–5099 (2006).

    CAS  Article  Google Scholar 

  25. 25

    Baumgart, T., Hess, S.T. & Webb, W.W. Nature 425, 821–824 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Shahinian, S. & Silvius, J.R. Biochemistry 34, 3813–3822 (1995).

    CAS  Article  Google Scholar 

  27. 27

    Chiu, V.K. et al. J. Biol. Chem. 279, 7346–7352 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Hughes, L.D., Rawle, R.J. & Boxer, S.G. PLoS ONE 9, e87649 (2014).

    Article  Google Scholar 

  29. 29

    Veatch, S.L. & Keller, S.L. Biochim. Biophys. Acta. 1746, 172–185 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Bhatia, V.K. et al. EMBO J. 28, 3303–3314 (2009).

    CAS  Article  Google Scholar 

  31. 31

    Bhatia, V.K., Hatzakis, N.S. & Stamou, D. Semin. Cell Dev. Biol. 21, 381–390 (2010).

    CAS  Article  Google Scholar 

  32. 32

    Rocks, O. et al. Science 307, 1746–1752 (2005).

    CAS  Article  Google Scholar 

  33. 33

    Larsen, J., Hatzakis, N.S. & Stamou, D. J. Am. Chem. Soc. 133, 10685–10687 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Elizondo, E. et al. J. Am. Chem. Soc. 134, 1918–1921 (2012).

    CAS  Article  Google Scholar 

  35. 35

    Silvius, J.R. Biochim. Biophys. Acta. 1746, 193–202 (2005).

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by the Lundbeck Foundation Center for Biomembranes in Nanomedicine, the Danish Councils for Independent and Strategic Research and the University of Copenhagen programs of excellence, 'Single-Molecule Nanoscience', 'BioScaRT' and 'UNIK-Synthetic Biology'. I.S. would like to acknowledge support from the U.S. National Science Foundation under grant no. CBET-1403058, and M.J.U acknowledges support from the US National Institutes of Health under grant no. P20GM103499.

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D.S. conceived the strategy and was responsible for the overall project management. D.S., N.S.H., J.B.L. and M.B.J designed all experiments, which were performed by J.B.L. and M.B.J with help from N.S.H. and V.K.B. S.L.P. and K.J.J. synthesized and purified tN-Ras. M.J.U. and I.S. performed theoretical calculations of anchor partitioning. J.B.L., D.S., L.I. and N.S.H. wrote the manuscript. D.S. and N.S.H. supervised the project. All authors discussed the results and commented on the manuscript at all stages.

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Correspondence to Dimitrios Stamou.

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The authors declare no competing financial interests.

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Supplementary Results and Supplementary Figures 1–14. (PDF 4117 kb)

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Larsen, J., Jensen, M., Bhatia, V. et al. Membrane curvature enables N-Ras lipid anchor sorting to liquid-ordered membrane phases. Nat Chem Biol 11, 192–194 (2015). https://doi.org/10.1038/nchembio.1733

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