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  • 1. Role of Membrane Lipid Rafts in Signal Transduction By Upendar Rao Golla 1220106
  • 2. Outline  What are lipid rafts?  Why do they form?  What methods are used to study lipid rafts?  What effects do they have on eukaryotes?  Why all the controversy?
  • 3. Membrane: Its Components
  • 4. What are Lipid Rafts ? “Lipid rafts are small (10-200nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched domains that compartmentalize cellular processes”
  • 5. Cell membrane
  • 6. Examples of lipid and protein domains in cell membranes Single domains, enriched in the fluorescent lipid analogue DMPECy5 Cholesterol-rich domains indirect immunofluorescence microscopy Lipid domains with greater relative order than the bulk membrane, visualized in living macrophages with the fluorescent probe, Laurdan. The warmer pseudocolours represent more ordered regions Domains formed by the proton–argenine symporter transporter (Can1p–GFP) The scale bars represent 1 μm in a, and 5 μm in c and d.
  • 7. Types of lipid rafts: Two • Caveolae: small, flaskshaped invaginations of the plasma membrane enriched in caveolin • Planar lipid rafts: found in neurons and enriched in flotillin • Caveolin and flotillin recruit signaling proteins • Signaling can be promoted or dampened
  • 8. Raft Proteins • True resident proteins – GPI-anchored proteins-prion protein (PrPc) – Caveolin – Flotillin • Signaling proteins – G-protein, non-receptor tyrosine kinases • Cytoskeletal/Adhesion proteins – actin, myosin, vinculin, cofilin, cadherin, ezrin
  • 9. How to name Lipid Rafts ?
  • 10. Why do they form?
  • 11. Why do they form? Cholesterol • Cholesterol is the dynamic “glue” that holds the raft together – Saturation – Hydroxyl H-bonding with amide • Up to 25% of cholesterol is found in the brain…CNS? • When removed, most proteins dissociate from rafts
  • 12. How to Identify Rafts ?
  • 13. How to Modify Rafts ?
  • 14. Rafts in Signal Transduction ?
  • 15. How Signaling Initiated Through Rafts ?
  • 16. Disorders & Diseases • HIV virus – Budding may occur from lipid rafts • Mood disorders – Therapeutic efficacy of antidepressants • Alzheimer’s disease – Platforms for production of amyloid-β (neurotoxic protein) • Prion disorder – Normal prion protein (PrPc) is converted to abnormal proteins (PrPsc) in lipid rafts (GPI anchor required)
  • 17. Why all the controversy? • Problems with biomembranes – Lipid rafts are too small to be resolved by light microscopy – Difficult to study lipid rafts in intact cells – Not in thermodynamic equilibrium • Problems with synthetic membranes – – – – Lower concentration of proteins Difficult to model membrane-cytoskeletal interactions Lack natural lipid asymmetry Studied under equilibrium conditions
  • 18. Works Cited • • • • • • • • • • • • Allen, John A. "Lipid raft microdomains and neurotransmitter signaling." Nature 8 (2007): 128-40. Benarroch, Eduardo E. "Lipid rafts, protein scaffolds, and neurologic disease." Neurology 69 (2007): 1635-639. Hamasaki, Dr. Toshikazu. "Tutorial 2, Plasma Membrane." UCLA. 22 Feb. 2009. Jacobson, Ken. "Lipid rafts: at a crossroad between cell biology and physics." Nature Cell Biology 9 (2007): 7-13. Jacques Fantini, Nicolas Garmy, Radhia Mahfoud and Nouara Yahi (2002) Lipid rafts: structure, function and role in HIV, Alzheimer’s and prion diseases. Exp. Rev. Mol. Med. 20 December, http://www.expertreviews.org/02005392h.htm Korade, Zeljka. "Lipid rafts, cholesterol, and the brain." Neuropharmacology 55 (2008): 1265273. Luckey, Mary. Membrane Structural Biology : With Biochemical and Biophysical Foundations. New York: Cambridge UP, 2008. Pike, Linda J. "The Challenge of Lipid Rafts." Journal of Lipid Research Oct (2008): 1-17. Simons, Kai, and Ehehalt, R. "Cholesterol, lipid rafts, and disease." The Journal of Clinical Invesigation 110 (2002): 597-603. Simons, Kai. "Lipid Rafts and Signal Transduction." Nature Reviews 1 (2000): 31-41. Simons, Kai. "Model Systems, Lipid Rafts, and Cell Membranes." Annu. Rev. Biophys. Biomol. Struct. 33 (2004): 269-95. Video: Viel, A., Lue R.A., “Inner life of the cell.” The president and Fellows of Harvard College (2007) http://multimedia.mcb.harvard.edu/anim_innerlife.html