The role of membrane lipid rafts in Signal transduction

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 ?

14. How to Modify Rafts ?

16. Rafts in Signal Transduction ?

17. How Signaling Initiated Through Rafts ?

18. 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)

19. 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

20. Works Cited
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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