Biology Reference
In-Depth Information
INTRODUCTION AND RATIONALE
The fluid mosaic model of biological membranes by
Singer and Nicolson (1972)
described the membrane as a primarily lipid matrix with proteins distributed
randomly throughout (
Singer & Nicolson, 1972
). However, shortly thereafter,
it was proposed that membranes contain “clusters of lipids,” these clusters
being “quasicrystalline” regions surrounded by more freely dispersed liquid
crystalline lipid molecules. This concept of membrane lipid microdomains was
refined to claim that these clusters would contain “lipids in a more ordered state.”
More importantly, the organization of lipids into membrane microdomains
provided an additional conceptual framework for membrane heterogeneity
across cellular subcompartments and thus the possibility of structural and func-
tional significance for these microdomains (
Karnovsky, Kleinfeld, Hoover, &
Klausner, 1982
).
Since its original proposal, the concept of membrane microdomains has been bet-
ter characterized at the molecular level. Under the term of lipid rafts, membrane
microdomains were described as being resistant to extraction by nonionic detergents
and enriched in cholesterol and glycosphingolipids (
Pike, 2009
). The term detergent-
insoluble microdomains is more encompassing of its heterogeneity in composition
than lipid rafts, as some of these microdomains may be selectively enriched for other
phospholipids. For simplicity, we will be using both indistinguishably in this chapter.
Lipid raft structures were thought to be stably held together by lipid-lipid interactions
(
Pike, 2009
). It has also become clear that lipid rafts are heterogeneous and dynamic
sterol- and sphingolipid-enriched nanoscale microdomains that compartmentalize cel-
lular processes (
Pike, 2009
), including membrane trafficking, signal transduction, and
cell polarization (
Lingwood, Kaiser, Levental, & Simons, 2009
). These microdomains
are ordered assemblies of specific proteins in which the meta-stable resting state can be
activated to coalesce by specific lipid-lipid, lipid-protein, and protein-protein inter-
actions (
Lingwood & Simons, 2010; Simons &Gerl, 2010; Simons & Sampaio, 2011
).
The compartmentalization of the plasma membrane into detergent-insoluble
microdomains is a very dynamic process. For example, in T cells, the formation
of an immunologic synapse correlates with clustering of glycolipid-enriched
microdomains. These microdomains are enriched with signaling molecules critical
for the initiation and sustainability of T cell antigen receptor mediated signaling such
as lck, linker for activation of T cells (LAT), and protein kinase C theta, and their
biological integrity is essential for proper T cell antigen receptor mediated signaling
(
Bi et al., 2001; Viola, Schroeder, Sakakibara, & Lanzavecchia, 1999; Xavier,
Brennan, Li, McCormack, & Seed, 1998; Zhang, Trible, & Samelson, 1998
). Lipid
rafts move into the immunologic synapse in response to CD3 and CD28 ligation, and
formation of these microdomains is important for normal signaling leading to T cell
activation. Lipid rafts also contain regulators of signaling such as CTLA-4, a nega-
tive regulator of T cell activation that partitions within lipid rafts and relocates to the
immunologic synapse (
Darlington et al., 2002
).
