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Cholesterol Structure in Lipid Rafts

Cholesterol Structure in Lipid Rafts. Laura Toppozini CAP Congress 2014 June 19, 2014. Cholesterol in Lipid Membranes. Mosaic model: Lipids, cholesterol, and proteins homogeneously mixed. Singer and Nicholson, 1972. Lipid raft model: Cholesterol-rich domains. Simons, 1997.

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Cholesterol Structure in Lipid Rafts

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  1. Cholesterol Structure in Lipid Rafts Laura Toppozini CAP Congress 2014 June 19, 2014

  2. Cholesterol in Lipid Membranes Mosaic model: Lipids, cholesterol, and proteins homogeneously mixed Singer and Nicholson, 1972 Lipid raft model: Cholesterol-rich domains Simons, 1997 What is cholesterol’s role in rafts?

  3. Project Details • What is cholesterol’s role in lipid membranes? • Can we see raft formation in a binary system? • What can binary system rafts elucidate about rafts in biological membranes? Neutron experiment at Canadian Neutron Beam Centre Coarse-grained MD simulations from collaborators at University of Mainz Neutron diffraction with stacked, oriented bilayers 20,000- molecule simulations L Toppozini, S Meinhardt, CL Armstrong, Z Yamani, N Kucerka, F Schmid, MC Rheinstadter. The Structure of Cholesterol in Lipid Rafts. Submitted, under review.

  4. Simulation: CG Molecular Dynamics ~40Å 20 mol% Liquid-ordered phase Liquid-ordered phase ~100Å 60 mol%

  5. Experiment: Neutron Scattering Larger λ { nm superresolution Smaller λ

  6. Cholesterol in Lipid Membranes 32.5% cholesterol Liquid–ordered phase

  7. Selective Deuteration Selectively highlight molecules

  8. Cholesterol Structure

  9. Cholesterol Structure Liquid-Disordered Cholesterol-lipid complexes Umbrella model Huang & Feigenson. Biophys J. 1999 76(4):2142-57

  10. Cholesterol Structure Ordered-Complexes -Ordered lipid-cholesterol complexes -Monoclinic unit cell a=b= 11Å α= 131˚ Cholesterol Plaques -Cholesterol bilayers/plaques -Triclinic unit cell a=b=12.8 Å α=95˚β=91.9˚γ=98.1˚

  11. Cholesterol Structures in Rafts The liquid-ordered phase of a binary system is heterogeneous Liquid disordered Observation of three coexisting cholesterol structures in the lo phase: Ordered lipid/cholesterol Small, (~10nm) transient (~100ns) structures are observed in lipid-cholesterol system Cholesterol plaques Domains in binary systems may be nuclei which lead to rafts in biological membranes.

  12. Acknowledgements MaikelC.Rheinstadter Clare Armstrong Norbert Kucerka Zahra Yamani Sebastian Meinhardt FriederikeSchmid

  13. Lipid Structure Liquid-disorderedfluid-like, hexagonal lipid structure alipid-raft blipid-raft Liquid-Ordered Rafts Gel-like monoclinic lipid structure of lipids in the rafts.

  14. Simulations: changing chemical potential

  15. Lipid/cholesterol phase diagram

  16. Membranes, Rafts, and Scattering Hydrated lipid bilayers have diffusive motion: signals are weak ~3000 bilayers/wafer give larger signals • Typical neutron scattering setup • gives large spatial averaging • Gives bulk structure • Are small structures being formed but averaged over?

  17. Measurement of Rafts neutron ξ ξ wave package ξ ξ Long coherence length Short coherence length

  18. Condensation and the Umbrella Model • Phospholipid head-group acts as umbrella, shields hydrophobic regions of cholesterol • Cholesterol proximity suppresses tail fluctuations • These complexes may form domains in lo phase at moderate cholesterol concentrations

  19. Experiment: Neutron Scattering • Change coherence length in-situ by changing wavelength • Large ξ setup: averaging over large areas. • Smaller ξ setup: integrates more efficiently over smaller structures

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