Biological

Membranes

I. OVERVIEW

Membranes form the outer boundary of individual cells and of certain

organelles. Plasma membranes are the selectively permeable struc­
tures of cells that separate interiors from the extracellular environment.
Certain molecules are permitted to enter and exit the cell by transport
across the plasma membrane.
Plasma membranes are composed of lipids and proteins that form their
structure and also facilitate cell function. For example, adhesion and sig­
naling are cellular processes initiated at the plasma membrane. Plasma
membranes also serve as attachment points for intracellular cytoskeletal
proteins and for components of the extracellular matrix outside of cells.
The basic structure of a biological membrane is a phospholipid bilayer
(Figure 3.1). Two antiparallel sheets of phospholipids form the membrane
that surrounds the inner contents of the cell. The phospholipid membrane
layer closest to the cytosol is the inner leaflet while the layer closest to
the exterior environment is the outer leaflet. Cholesterol molecules interca­
late or fit between phospholipid molecules. Proteins also associate with the
membrane to enable biological functions according to the need of the partic­
ular cell, including transport of or response to particular signaling molecules.
All these membrane components are important in creating the membrane
and establishing a stable, yet dynamic, barrier to maintain the internal envi­
ronment of the cell while facilitating the biological function of the cell.

Figure 3.1
Plasma membrane structure.

31
32 3. Biological Membranes

II. COMPONENTS

All cell membranes, including plasma membranes, organelle mem­

branes, and intracellular vesicles (membrane-enclosed structures inside
the plasma membrane), are composed of the same materials. The major
components of all biological membranes are lipids and proteins. Several
forms of lipids exist to provide structure, support, and function for the
membrane. Membrane proteins also play both structural and functional
roles.

A. Lipids
In most cell membranes, lipids are the most abundant type of macro­
molecule present. Plasma and organelle membranes contain between
40% and 80% lipid. These lipids provide both the basic structure and
the framework of the membrane and also regulate its function. Three
types of lipids are found in cell membranes: phospholipids, choles­
terol, and glycolipids.

1. Phospholipids: The most abundant of the membrane lipids are

the phospholipids. These are polar, ionic compounds that are
amphipathic in nature. That is, they have both hydrophilic and
hydrophobic components. The hydrophilic or polar portion is in
the “head group” (Figure 3.2). Within the head group is the phos­
phate and an alcohol that is attached to it. The alcohol can be
serine, ethanolamine, inositol, or choline. Names of phospholipids
then include phosphatidylserine, phosphatidylethanolam ine,
phosphatidylinositol, and phosphatidylcholine. While all these
phospholipids contain a molecule called glycerol, the membrane
Figure 3.2
phospholipid sphingom yelin has the alcohol choline in its head
Structures of some phospholipids.
group and contains sphingosine instead of glycerol (Figure 3.3).
The hydrophobic portion of the phospholipid is a long, hydrocar­
Ether Unsaturated bon fatty acid tail. While the polar head groups of the outer leaflet
linkage
r i extend outward toward the environment, the fatty acid tails extend
c h 2- o - c h = ch
I inward to the interior of the phospholipid bilayer. Fatty acids may
-C -O -C H o be saturated, containing the maximum number of hydrogen atoms
II
CH2- O - P - 0CH2CH2 - n h 3 bound to carbon atoms, or unsaturated with one or more carbon-
Acyl
group o- to-carbon double bonds, (see also U R Biochemistry, Chapter 17).
Glycerol backbone The length of the fatty acid chains and their degree of saturation
Phosphatldylethanolamlne impact the membrane structure. Fatty acid chains in membranes
normally undergo motions such as flexion (bending or flexing),
rotation, and lateral movement (Figure 3.4). Whenever a carbon-
CH3 to-carbon double bond exists, there is a kink in the chain, reduc­
RH CH2CH2N+
I
ing some types of motion and preventing the fatty acids from
ch3 packing tightly together. Phospholipids in plasma membranes of
healthy cells do not migrate or flip-flop from one leaflet to the other.
-----Choline
(However, during the process of programmed cell death, enzymes
catalyze the movement of phosphatidylserine from the inner leaflet
to the outer leaflet [see also Chapter 23].)
Fatty acids
2. Cholesterol: Another major component of cell membranes is
cholesterol. An amphipathic molecule, cholesterol contains a polar
Figure 3.3 hydroxyl group as well as a hydrophobic steroid ring and attached
Glycerol (A) and sphingosine (B)
backbones in phospholipids.
II. Components 33

hydrocarbon (Figure 3.5). Cholesterol is dispersed throughout

cell membranes, intercalating between phospholipids. Its polar
hydroxyl group is near the polar head groups of the phospho­
lipids while the steroid ring and hydrocarbon tails of cholesterol
are oriented parallel to those of the phospholipids (Figure 3.6).
Cholesterol fits into the spaces created by the kinks of the unsatu­
rated fatty acid tails, decreasing the ability of those fatty acids to
undergo motion and therefore causing stiffening and strengthen­
ing of the membrane.

3. G lycolipids: Glycolipids are lipids with attached carbohydrate,

and are found in cell membranes in lower concentration than phos­
pholipids and cholesterol. The carbohydrate portion of a glycolipid
is always oriented toward the outside of the cell, projecting into
the environment. Glycolipids help to form the carbohydrate coat
observed on cells and are involved in cell-to-cell interactions. They
are a source of blood group antigens and also can act as receptors Figure 3.4
for toxins including those from cholera and tetanus. Types of motions of membrane
phospholipids.
B. Proteins
While lipids form the main structure of the membrane, proteins are
largely responsible for many biological functions of the membrane.
For example, some membrane proteins function in transport of mate­
rials into and out of cells (see Unit III). Others serve as receptors for
hormones or growth factors (see Unit IV). The types of proteins within
a plasma membrane vary depending on the cell type. However, all
membrane proteins are associated with membrane in one of three
main ways.

1. Membrane associations of proteins: While some proteins span

the membrane with structures that cross both bilayers and extend
from the environment to the cytoplasm, others are anchored to
membrane lipids and still others are only peripherally associated Figure 3.5
with the cytosolic side of a plasma membrane (Figure 3.7). Structure of cholesterol.

a. Transmembrane proteins: Transmembrane proteins are

embedded within the lipid bilayer of the membrane and extend
from the environment into the cytosol. Some transmembrane
proteins contain one transmembrane region while others con­
tain several. Some hormone receptors are proteins with seven
distinct membrane-spanning regions (7-pass or 7-loop trans­
membrane receptors). All transmembrane proteins contain
both hydrophilic and hydrophobic components, based on the
chemical nature of their amino acid constituents. These pro­
teins are oriented with their hydrophilic portions in contact with
the aqueous exterior environment and with the cytosol and their
hydrophobic portions in contact with the fatty acid tails of the
phospholipids. It is usually the case that proteins cross cellular
Figure 3.6
membranes by adopting a structure containing one or more a
Cholesterol and phospholipids in
helices (see UR Biochemistry, Chapters 1 and 2 for a discus­ membranes.
sion of amino acid and protein structure).

b. Lipid-anchored proteins: Members of the second category

of membrane proteins are lipid-anchored proteins that are
attached covalently to a portion of a lipid without entering the
core portion of the bilayer of the membrane.
34 3. Biological Membranes

Exterior
environment Alpha-helical protein Ion channel
Transmembrane
Phospholipid bilayer
protein r-—
Outer
leaflet

Inner
leaflet

Lipid anchored
protein Peripheral
membrane proteins I
Cytosol

Figure 3.7
Protein associations with membranes.

Both transmembrane and lipid-anchored proteins are integral

membrane proteins since they can only be removed from a
membrane by disrupting the entire membrane structure.

c. Peripheral membrane proteins: Proteins in the third category

are peripheral membrane proteins, which are located on the
cytosolic side of the membrane and only attach indirectly to the
lipid of the membrane. Such proteins bind to other membrane
proteins that are directly attached to the lipids. Cytoskeletal
proteins, including those involved in forming the spectrin mem­
brane skeleton of erythrocytes, are examples of peripheral
membrane proteins (see Chapter 4).

2. Membrane protein functions: Membrane proteins enable cells

to function as members of a tissue (Figure 3.8). For example, cell
adhesion molecules are proteins that extend to the surface of

Exterior
environment
Phospholipid bilayer

Outer
leaflet

Inner
leaflet

Cytosol

Figure 3.8
Functions of membrane proteins.
III. Structure 35

cells and facilitate cell-to-cell contact (see Chapter 2). Other mem­
brane proteins function as ion channels and transport proteins
to enable molecules to enter and exit a cell (see Unit III). Membrane
proteins that are ligand receptors enable cells to respond to hor­
mones and other signaling molecules (see Unit IV). The preceding
examples of membrane proteins are of integral, transmembrane
proteins whose structures span the bilayer. Lipid-anchored mem­
brane proteins include the G proteins, which participate in cell sig­
naling in response to certain ligands (see Chapter 17). Peripheral
membrane proteins include cytoskeletal proteins that attach to
the membrane and regulate its shape and stabilize its structure
(see Chapter 4). Some other peripheral membrane proteins are
also involved in cell signaling and include enzymes attached to the
inner membrane leaflet that are activated after a hormone binds to
a protein receptor (see Chapter 17).

III. STRUCTURE

The proteins and lipids of a cellular membrane are arranged in a certain

way to form a stable outer structure of the cell. The membrane compo­
nents, including lipids and proteins, are not fixed rigidly into a particular
location. Both can exhibit several types of motions as described previ­
ously for phospholipids (see Figure 3.4). Membrane proteins can also
move laterally and can rotate. Owing to the composition and dynamic
nature of membrane components, the membrane is largely fluid in nature,
as opposed to solid or rigid. Despite its fluidity, the membrane structure is
very stable and supportive for the cell. The arrangement of the phospho­
lipids provides the basic structure that is then augmented by cholesterol,
with functional roles played by proteins.

A. Bilayer arrangement Figure 3.9

Membrane phospholipids are oriented with their hydrophobic fatty Arrangements of membrane
phospholipids in a bilayer.
acid tails facing away from the polar, aqueous fluids of both the
cytosol and the environment (such as blood or other cellular fluids
Outer leaflet
including lymph). The hydrophilic portions of the phospholipids are
oriented toward the polar environment. Two layers of phospholipids
are required to achieve this structure (Figure 3.9). The phospholipids
of each layer are found in opposite orientation to each other. While the
polar head groups of one layer (outer leaflet) of phospholipids face
the exterior, those of the other layer (inner leaflet) face the interior. A
nonpolar or hydrophobic central region results where the fatty acid
tails of the two layers are in contact with each other.

B. Asymmetry
The fatty acid tails of all the phospholipids are structurally very similar
to each other, and the identity of an individual phospholipid molecule is
determined by the alcohol within its head group, as mentioned previously
(Section II.A.1 above). Some phospholipids are found on the outer leaf­
I Phosphatidylethanolamine \
Phosphatidylserine Phosphatidylinositol
let while others are more commonly seen on the inner leaflet. In plasma
membranes of most human cells, phosphatidylcholine and sphingo­ Inner leaflet
myelin are in the outer leaflet oriented toward the environment, while
phosphatidylserine, phosphatidylethanolamine, and phosphatidylino- Figure 3.10
sitol are in the inner leaflet oriented toward the cytosol (Figure 3.10). Asymmetry of membranes.
36 3. Biological Membranes

Exterior
environment

Undergoes Undergoes
lateral lateral
movement movement

Cytosol

Figure 3.11
Fluid mosaic model.
As also mentioned previously (Section II.A.1 above), during the pro­
cess of apoptosis or programmed cell death, phosphatidylserine is
transferred enzymatically from the inner leaflet to the outer leaflet of the
membrane. The presence of phosphatidylserine on the outer leaflet then
triggers phagocytic removal of the dying cells, emphasizing further that
the maintenance of membrane asymmetry is important for normal cell
function.
In addition to an asymmetric distribution of phospholipids between
the membrane leaflets, glycolipids are differentially arranged as well
and are always on the outer leaflet with their attached carbohydrate
projecting away from the cell. Glycoproteins are similarly oriented on
the outer leaflet with their carbohydrate portions projecting into the
environment. Peripheral membrane proteins are attached only to the
inner membrane leaflet, facing the cytoplasm. Therefore, the inner
and outer membrane leaflets have different compositions and each
has functions distinct from those of the other. Cholesterol, however,
can readily flip-flop or move from one leaflet to the other and is distrib­
uted on both sides of the membrane bilayer.

C. Fluid mosaic model

For several decades, the membrane model proposed by Singer and
Nicholson in 1972 has been used to describe plasma membranes.
The membrane is characterized as a fluid, owing to the ability of lip­
ids to diffuse laterally within the plane of the membrane. The overall
Exterior
structure is equated to a flowing sea. And, like a mosaic, membrane
environment proteins are dispersed throughout the membrane. Many of the mem­
brane proteins retain the ability to undergo lateral motion and are lik­
ened to icebergs floating within the sea of lipids (Figure 3.11).

D. Lipid rafts
Lipid rafts are specialized sphingolipid and cholesterol-enriched
microdomains within cell membranes (Figure 3.12). Functions of lipid
rafts include cholesterol transport, endocytosis, and signal transduc­
Cytosol
tion. The lipid raft hypothesis assumes that cholesterol combines with
glycosphingolipids (phospholipids that have straight acyl chains), to
Figure 3.12 form transient structures that appear as “rafts” floating in the phos­
Lipid raft. pholipid sea created by poorly ordered lipids of the surrounding
Study Questions 37

portions of the membrane. Fatty acid chains of phospholipids within

the rafts are extended and more tightly packed. Average sizes, distri­
butions, and lifespan of lipid rafts are not well defined, and the forces
that drive their formation are not completely understood. There seem
to be strong attractions between sphingolipids and cholesterol and
repulsion between phospholipids and the sphingolipids. The repulsive
forces likely play a major role in the formation of the rafts. It is difficult
to study lipid rafts in living cells and the structures are too small to
be observed by light microscopy; however, distinct types of lipid raft
structures are described.
Types of lipid rafts include planar, glycosphingolipid-enriched mem­
branes (GEM), and caveolae. Planar rafts are continuous with the
plane of the plasma membrane and lack any distinctive morphologi­
cal features. Caveolae, on the other hand, are flask-shaped inward
foldings of the plasma membrane that contain the protein caveolin.
The presence of caveolin causes a local change in morphology of
the membrane (Figure 3.13). Caveolae are found in a variety of tis­
sues, particularly in endothelial cells, but are absent from neuronal Figure 3.13
tissues. Many proteins and lipids are found in high concentrations in Caveolae.
caveolae, including arachidonic acid, a fatty acid involved in cell sig­
naling, certain growth factor receptors, integrins, and insulin recep­
tors, among others.

r ~\

Chapter Summary

• Plasma membranes are selectively permeable outermost structures of eukaryotic cells.

• All biological membranes have the same basic structure.
• Lipids are generally the most abundant type of macromolecule within cell membranes.
• Phospholipids and cholesterol are amphipathic lipids that form the basic structure of cell membranes.
• Proteins associated with membranes may be transmembrane, lipid anchored, or peripheral to the membrane.
• Membrane proteins function as ion channels, transport proteins, ligand receptors, and components of the cytoskeleton.
• The basic membrane structure is that of a phospholipid bilayer.
• An asymmetric distribution of phospholipids results in each side or leaflet of the membrane having distinctive characteristics.
• Lipids and proteins in the membrane are not static but retain the ability to undergo motion within the membrane.
• The fluid mosaic model describes the fluid phospholipid “sea” in which proteins appear to be distributed in a mosaic
pattern and to float within the sea of the lipids.
• Membrane microdomains known as lipid rafts are membrane regions enriched in specialized lipids that function in cho­
lesterol transport, endocytosis, and signal transduction.
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