Lipid Raft and Signal
Transduction
Tao Chen
Lipid Raft
• A cholesterol-enriched microdomain in cell
membrane.
• A liquid-ordered phase dispersed in a liquid
disordered matrix of cell membrane, which is
thought to minimize the free energy between the
two phases.
• Can include and exclude proteins to variable
extents.
• Resistent to non-ionic detergents, such as Triton
X-100 or Brij-98 at low temperatures (e.g., 4℃).
• Also called DRM, DIG, DIC, GPI domain,
Glycosphingolipid signaling domain, caveolae-like
domain, microdomain, LDM, lipid-ordered domain,
DIM, GEM and TIFF.
A Intracellular space or cytosol
B Extracellular space or vesicle/Golgi apparatus
lumen
(1)Non-raft membrane (2)Lipid raft (3)Lipid raft
associated transmembrane protein (4)Non-raft
membrane protein
(5)Glycosylation modifications (6)GPI-anchored
protein (7)Cholesterol (8)Glycolipid
Techniques to Identify Lipid
Raft:
Signal Transduction
• Signal transduction refers to any process by which
a cell converts one kind of signal or stimulus into
another.
• Ligand bind to receptor
Receptor change its
conformation
Enzyme bind to receptor
Enzyme is activated
Red: chemical messenger
Yellow: transmembrane protein
Purple: cell membrane
Green: enzyme
http://www.youtube.com/watch?v=tMMrTRnFdI4
• Through the connection of
raft proteins and
interacting proteins to
form a complex, resulting
in the activation of
signalling cascade.
(1) Single Rafts Model
(a) Receptors associated at steady
state with lipid rafts could be activated through
ligand binding
(b) Individual receptors with weak raft affinity could
oligomerize on ligand binding, and this would lead to
an increased residency time in rafts.
(2) Clustered Rafts Model
Activated receptors could recruit
cross linking proteins that bind to proteins in other
rafts, and this would result in raft coalescence.
• Clustering of lipid raft can occur both
extracellularly, within the membrane, and in the
cytosol. It can also occur through GPI anchored
proteins, either as a primary or co-stimulatory
response.
• These two models are not mutually exclusive.
T-Cell Antigen Receptor
Signalling
• The T cell receptor or TCR is a heterodimer
consisting of an alpha and beta chain.
• Alpha, beta heterdimer associate with CD3
complex and ζ homodimer which contain
cytoplasmic ITAM motifs (immune receptor
tyrosine-based activation motifs).
• Ligand-induced
receptor dimerization of
TCR/CD3
• Phosphorylation of the
receptor’s ITAMs by
Src-family protein
tyrosine kinases
• Phosphorylated ITAMs act as a membrane docking
site for ZAP-70
• ZAP-70 activate other proteins such as LAT, a raftassociated adaptor, through cross linking, LAT can
recruit other proteins into the raft and further
amplify the signal.
• Cytosolic kinase Csk bind to raft-associated protein
CBP and then inactivate the Src-family kinases
through phosphorylation
Open Issues:
• Raft composition
• Whether more than one kind of raft exists on the
cell surface of different cell types.
• Understanding the nature of individual rafts.
• How single rafts are crosslinked to form clustered
rafts during signal transduction.
References
• Kai Simons and Derek Toomre, Lipid Rafts and Signal
Transduction, Nature Reviews-Molecular Cell Biology,
2000, 1, 31-41
• Brown D A, London E, Functions of Lipid Rafts in
Biological Membranes, Annu. Rev. Cell. Dev. Biol,
1998, 14, 111-136
• Schroeder R, London E, Brown D, Interactions
between saturated acyl chains confer detergent
resistent on lipids and
glycosylphosphatidylinositol(GPI)-anchored proteins:
GPI-anchored proteins in liposomes and cells show
similar behavior, Proc. Natl Acad. Sci. USA, 1994, 91,
12130-12134
• Zhang W, Trible R P, Samelson L E, LAT
palmitoylation: its essential role in membrane
microdomain targeting and tyrosine phosphorylation
during T-cell activation, immunity, 1998, 9, 239-246