Cell News 3/2013
14
A new generation of physical models for
the plasma membrane to study inter-leaflet
coupling and trans-membrane signaling
Salvatore Chiantia
Abstract
Cellular membranes are complex biological entities which per-
form a wide range of functions. The lateral organization of lipids
and receptors of the plasma membrane (PM) into ordered do-
mains (e.g. raft domains) is involved in several biological proces-
ses such as cell-cell communication or viral infections.
In order to understand the structure and function of complex
biological membranes, artificial bilayers have been used in the
past as simple and well-defined physical models. Nevertheless,
until recently, such model bilayers have not taken into account
the important compositional asymmetry between inner and ou-
ter leaflets of PM.
The introduction of the novel asymmetric PM models descri-
bed here represents an important step forward in the field of
membrane biophysics and will provide the chance to understand
in general how the structure and function of lipid-protein do-
mains are affected by leaflet compositional asymmetry and by
the coupling between leaflets.
Trans-membrane compositional asymmetry of
biological membranes
Cellular membranes, and in particular the plasma membra-
ne (PM), are characterized by a transversal lipid composition
asymmetry. In other words, while the cytoplasmic leaflet of
the PM contains mostly unsaturated aminophospholipids (e.g.
phosphatidylserine (PS), phosphatidylethanolamine (PE)) and
inositol-based phospholipids, the outer leaflet is rich in satura-
ted sphingolipids, such as sphingomyelin (SM) and gangliosides
(Bretscher, 1972; Devaux, 1991). Although this specific lipid dis-
tribution was clearly demonstrated for the PM of erythrocytes
at first (Rothman and Lenard, 1977), membrane asymmetry was
eventually also observed in several other biological systems,
including viruses, fibroblast phagosomes, platelets and other
membranes of eukaryotic cells (Rothman and Lenard, 1977; Fa-
deel and Xue, 2009). The trans-membrane distribution of cho-
lesterol, which can quickly flip between inner and outer leaflet,
remains controversial.
Since a lipid bilayer with an asymmetric composition is not in
an equilibrium state, a complex ATP-dependent protein machi-
nery is required to catalyze and direct the otherwise slow and
random trans-bilayer dynamics. Why would a cell invest such
a considerable amount of energy to generate and maintain a
specific asymmetric lipid distribution in the PM? Evidence accu-
mulated that PM asymmetry is in fact involved in a large num-
ber of physiological and pathological events. The enrichment of
PS in the cytoplasmic leaflet is connected to cellular processes
RESEARCH NEWS
Figure 1. Membrane compositional asymmetry influences membrane curvature:
(A) Confocal fluorescence microscopy images of GUVs (symmetric composition) containing phosphatidylcholine, SM and cholesterol. Such lipid composi-
tion displays phase separation into ordered (raft-like) and disordered domains, shown in green and red respectively. Scale bar is 20 µm. B) SM in the outer
leaflet is enzymatically converted into ceramide (the enzyme is confined to the external milieu of the vesicles). Since ceramide has a negative intrinsic mo-
nolayer curvature, its accumulation in the outer leaflet of GUV modifies bilayer curvature, causing inward budding of the membrane. Scale bar is 2 µm. C)
After some minutes, the budding process is complete and the interior of GUVs is filled with small vesicles. Interestingly, the fact that the budded vesicles
are strongly labeled with the green fluorescent probe confirms that they originated selectively from the ordered raft-like domains of the membrane. Scale
bar is 10 µm. This simple mechanism seems to be involved in lipid sorting in endosomes (see text). Adapted from (Trajkovic et al., 2008).
