Structure of the Plasma Membrane

Like all other cellular membranes, the plasma membrane consists of both lipids and proteins.
The fundamental structure of the membrane is the phospholipid bilayer, which forms a stable
barrier between two aqueous compartments. In the case of the plasma membrane, these
compartments are the inside and the outside of the cell. Proteins embedded within the
phospholipid bilayer carry out the specific functions of the plasma membrane, including
selective transport of molecules and cell-cell recognition.

The Phospholipid Bilayer

The plasma membrane is the most thoroughly studied of all cell membranes, and it is largely
through investigations of the plasma membrane that our current concepts of membrane
structure have evolved. The plasma membranes of mammalian red blood cells (erythrocytes)
have been particularly useful as a model for studies of membrane structure. Mammalian red
blood cells do not contain nuclei or internal membranes, so they represent a source from which
pure plasma membranes can be easily isolated for biochemical analysis. Indeed, studies of the
red blood cell plasma membrane provided the first evidence that biological membranes consist
of lipid bilayers. In 1925, two Dutch scientists (E. Gorter and R. Grendel) extracted the
membrane lipids from a known number of red blood cells, corresponding to a known surface
area of plasma membrane. They then determined the surface area occupied by a monolayer of
the extracted lipid spread out at an air-water interface. The surface area of the lipid monolayer
turned out to be twice that occupied by the erythrocyte plasma membranes, leading to the
conclusion that the membranes consisted of lipid bilayers rather than monolayers.
The plasma membranes of animal cells contain four major phospholipids (phosphatidylcholine,
phosphatidylethanolamine, phosphatidylserine, and sphingomyelin), which together account
for more than half of the lipid in most membranes. These phospholipids are asymmetrically
distributed between the two halves of the membrane bilayer (Figure 12.2). The outer leaflet of
the plasma membrane consists mainly of phosphatidylcholine and sphingomyelin, whereas
phosphatidylethanolamine and phosphatidylserine are the predominant phospholipids of the
inner leaflet. A fifth phospholipid, phosphatidylinositol, is also localized to the inner half of
the plasma membrane. Although phosphatidylinositol is a quantitatively minor membrane
component, it plays an important role in cell signalling. The head groups of both
phosphatidylserine and phosphatidylinositol are negatively charged, so their predominance in
the inner leaflet results in a net negative charge on the cytosolic face of the plasma membrane.
Figure 12.2Lipid components of the plasma membrane
The outer leaflet consists predominantly of phosphatidylcholine, sphingomyelin, and glycolipids,
whereas the inner leaflet contains phosphatidylethanolamine, phosphatidylserine, and
phosphatidylinositol. Cholesterol is distributed in both leaflets. The net negative charge of the head
groups of phosphatidylserine and phosphatidylinositol is indicated.

In addition to the phospholipids, the plasma membranes of animal cells contain glycolipids and
cholesterol. The glycolipids are found exclusively in the outer leaflet of the plasma membrane,
with their carbohydrate portions exposed on the cell surface. They are relatively minor
membrane components, constituting only about 2% of the lipids of most plasma membranes.
Cholesterol, on the other hand, is a major membrane constituent of animal cells, being present
in about the same molar amounts as the phospholipids.
Two general features of phospholipid bilayers are critical to membrane function. First, the
structure of phospholipids is responsible for the basic function of membranes as barriers
between two aqueous compartments. Because the interior of the phospholipid bilayer is
occupied by hydrophobic fatty acid chains, the membrane is impermeable to water-soluble
molecules, including ions and most biological molecules. Second, bilayers of the naturally
occurring phospholipids are viscous fluids, not solids. The fatty acids of most natural
phospholipids have one or more double bonds, which introduce kinks into the hydrocarbon
chains and make them difficult to pack together. The long hydrocarbon chains of the fatty acids
therefore move freely in the interior of the membrane, so the membrane itself is soft and
flexible. In addition, both phospholipids and proteins are free to diffuse laterally within the
membrane—a property that is critical for many membrane functions.
Because of its rigid ring structure, cholesterol plays a distinct role in membrane structure.
Cholesterol will not form a membrane by itself, but inserts into a bilayer of phospholipids with
its polar hydroxyl group close to the phospholipid head groups (see Figure 12.2). Depending
on the temperature, cholesterol has distinct effects on membrane fluidity. At high temperatures,
cholesterol interferes with the movement of the phospholipid fatty acid chains, making the
outer part of the membrane less fluid and reducing its permeability to small molecules. At low
temperatures, however, cholesterol has the opposite effect: By interfering with interactions
between fatty acid chains, cholesterol prevents membranes from freezing and maintains
membrane fluidity. Although cholesterol is not present in bacteria, it is an essential component
of animal cell plasma membranes. Plant cells also lack cholesterol, but they contain related
compounds (sterols) that fulfill a similar function.
Recent studies suggest that not all lipids diffuse freely in the plasma membrane. Instead,
discrete membrane domains appear to be enriched in cholesterol and the sphingolipids
(sphingomyelin and glycolipids). These clusters of sphingolipids and cholesterol are thought
to form “rafts” that move laterally within the plasma membrane and may associate with specific
membrane proteins. Although the functions of lipid rafts remain to be understood, they may
play important roles in processes such as cell signaling and the uptake of extracellular
molecules by endocytosis.

Membrane Proteins
While lipids are the fundamental structural elements of membranes, proteins are responsible
for carrying out specific membrane functions. Most plasma membranes consist of
approximately 50% lipid and 50% protein by weight, with the carbohydrate portions of
glycolipids and glycoproteins constituting 5 to 10% of the membrane mass. Since proteins are
much larger than lipids, this percentage corresponds to about one protein molecule per every
50 to 100 molecules of lipid. In 1972, Jonathan Singer and Garth Nicolson proposed the fluid
mosaic model of membrane structure, which is now generally accepted as the basic paradigm
for the organization of all biological membranes. In this model, membranes are viewed as two-
dimensional fluids in which proteins are inserted into lipid bilayers (Figure 12.3).
Figure 12.3 Fluid mosaic model of the plasma membrane
Integral membrane proteins are inserted into the lipid bilayer, whereas peripheral proteins are bound
to the membrane indirectly by protein-protein interactions. Most integral membrane proteins are
transmembrane proteins, with portions exposed on both sides of the lipid bilayer. The extracellular
portions of these proteins are usually glycosylated, as are the peripheral membrane proteins bound to
the external face of the membrane.

Singer and Nicolson distinguished two classes of membrane-associated proteins, which they
called peripheral and integral membrane proteins. Peripheral membrane proteins were
operationally defined as proteins that dissociate from the membrane following treatments
with polar reagents, such as solutions of extreme pH or high salt concentration, that do not
disrupt the phospholipid bilayer. Once dissociated from the membrane, peripheral membrane
proteins are soluble in aqueous buffers. These proteins are not inserted into the hydrophobic
interior of the lipid bilayer. Instead, they are indirectly associated with membranes through
protein-protein interactions. These interactions frequently involve ionic bonds, which are
disrupted by extreme pH or high salt.
In contrast to the peripheral membrane proteins, integral membrane proteins can be released
only by treatments that disrupt the phospholipid bilayer. Portions of these integral membrane
proteins are inserted into the lipid bilayer, so they can be dissociated only by reagents that
disrupt hydrophobic interactions. The most commonly used reagents for solubilization of
integral membrane proteins are detergents, which are small amphipathic molecules
containing both hydrophobic and hydrophilic groups. The hydrophobic portions of detergents
displace the membrane lipids and bind to the hydrophobic portions of integral membrane
proteins. Because the other end of the detergent molecule is hydrophilic, the detergent-protein
complexes are soluble in aqueous solutions.