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Introductory article
Article Contents
The membranes of living cells support much of the functionality of biology. From the
subcellular level of organelles to the supercellular level of cellcell interactions, membranes
provide the structures necessary for biological function and organization, as well as
regulation of function.
Introduction
Membranes provide compartmentalization of cellular
function, control cellcell recognition, transduce extracellular signals to regulate internal cellular activity,
synthesize ATP, the common currency of cellular energy,
create pathways for controlled internal transport of
materials around the cell, enable and regulate all transport
of material between the inside and the outside of cells, as
well as a supporting a host of other cellular activities. In
eukaryotic cells, all the internal organelles are dened by
membranes. Consistent with this focus of cellular activity
on cell membranes, it is estimated that nearly half of all
expressed proteins are integral membrane proteins, and
many more are associated with cell membranes.
An appreciation of the many facets of cell membrane
structure and function can be gained by initially considering separately the two major components of cell membranes: the lipid bilayer and membrane proteins.
Structure
. Structure
. Function of Cell Membranes
. Mammalian Cell Membranes
. Other Biological Membranes
Lipid bilayer
The fundamental architecture of biological membranes is
based on the lipid bilayer. All biological membranes
contain the bilayer structure. The bilayer structure is in
turn based on the chemical structure of the lipid
constituents and the hydrophobic eect.
The hydrophobic eect is the most important inuence
on biological macromolecular structures (like proteins,
DNA and cell membranes) outside of the covalent bond.
The hydrophobic eect represents the high cost in free
energy (mostly entropy) of an encounter between water
and compounds such as hydrocarbons that cannot
participate (through hydrogen bond, for example) in the
structure of water. In such cases, water molecules must
organize (involving unfavourable entropy change) in
dynamic arrays, or cages, around such compounds. The
energy cost of forming these cages is so high that
hydrocarbons are excluded from water to a very high
degree. Thus, proteins will fold such that amino acids with
hydrocarbon-like side-chains will locate in the protein
Water
Water
Figure 1 Schematic representation of a lipid bilayer. The circles represent
the polar headgroups of the lipids and the lines connected to the circle
represent the hydrophobic hydrocarbon chains of the lipids. These
amphipathic molecules are dual nature: one end is hydrophilic and one end
is hydrophobic. They organize to as to limit the exposure of the
hydrophobic portions to the aqueous phase that is found on both sides of
the membrane.
membrane proteins, although much remains to be understood about how this is achieved.
The lipid bilayer is relatively impermeable to solutes,
and thus forms an eective barrier to movement of solutes
from one side of a cell membrane to another. This
fundamental characteristic imparts to cell membranes
one of the properties crucial to cell survival, the compartmentalization of cell function. Since solutes cannot pass
through the lipid bilayer, the only way solutes can get into
and out of a cell is through transport functions catalysed
and regulated by membrane proteins. Thus, solute movements between cellular compartments and into and out of
the cell are tightly controlled by the cell membranes.
The lipid bilayer of cellular membranes allows lateral
movement, or diusion, of lipids and many proteins in the
plane of the membrane. Lateral diusion of the proteins
can be important to protein function, allowing some
proteins to properly associate for expression of their
activity. In some cases, the lateral movement of membrane
components is restricted. This can lead to patches of
dierent composition in the plane of the membrane (rafts).
The most distinctive dierences in composition within a
membrane are found between the two faces of the
membrane. The lipid composition on one side of the
bilayer of a cell membrane is often dierent from that on
the other side of the bilayer. Thus, for example, in the
mammalian erythrocyte, lipids with choline in their headgroup face predominantly to the exterior, while lipids with
amino functions in their headgroups face the cytoplasm of
the cell. This asymmetry in lipid composition is most
striking in the erythrocyte plasma membrane and is usually
much less pronounced in other cell membranes.
Cholesterol is an essential lipid in mammalian cells and
in those cells is found predominantly in the plasma
membrane. Yeast have ergosterol as their essential sterol.
Plant cells have dierent sterols, such as sitosterol. The
specicity of sterol is likely due to the interaction between
specic sterol structures and particular membrane proteins
in these cells to regulate crucial cellular functions. Some
bacteria have sterols and others do not require this lipid for
growth. Enveloped viruses (viruses with a membrane
around the nucleocapsid) will have sterols characteristic
of the cell in which they propagate.
Membrane proteins
Proteins are linear polymers of amino acids. Some of the
amino acids are hydrophobic and some are hydrophilic.
The hydrophobic eect controls protein structure as it
controls bilayer structure. The structure of water-soluble
proteins is particularly simple in this regard. After
synthesis, when these linear polymers of amino acids fold
into functional proteins, the hydrophobic amino acids
must be sequestered largely in the interior of the protein so
as not to encounter water, while the hydrophilic amino
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Integral
Anchored Transmembrane
Associated
Skeletal
Peripheral
Figure 3 Schematic representation of the classes of membrane proteins.
The darker shaded regions are the hydrophobic portions of these
membrane proteins and the clear horizontal box represents the lipid
bilayer. The transmembrane proteins are exposed on both sides of the
membrane; anchored membrane proteins penetrate only one-half of the
lipid bilayer; associated membrane proteins bind to transmembrane
proteins as part of a complex; and skeletal membrane proteins form a
network underneath the plasma membrane that can give shape to a cell.
Compartmentalization
Because of the relative impermeability of cell membranes,
the cell membranes separate compartments within the cell
and separate the inside of the cell from the outside of the
cell. This allows the individual compartments to have
dierent compositions, which can be critical to cell
function. For example, the outside of mammalian cells is
relatively high in sodium while the cytoplasm is relatively
low in sodium. The plasma membrane keeps the two
compartments separate; this is critical, for example, to
maintaining ion gradients required for action potentials.
Another example can be seen in the sequestration of
degradative enzymes in the lysosome by the lysosomal
membrane.
Transport
Because of the relatively impermeable nature of the lipid
bilayer, cellular compartments separated by membranes of
the cellular organelles can have signicantly dierent
compositions. For example, the cytoplasm of the cell is
depleted in calcium relative to the lumen of the endoplasmic reticulum and relative to the outside of the cell. The
cytoplasm of a mammalian cell has a signicantly lower
sodium concentration than the outside of the cell. How are
these dierences in composition established and maintained? The answer lies in the transport function of
biological membranes. Membranes tightly regulate the
composition of the compartments they enclose by controlling the access to these compartments for various solutes.
Transport across membranes can be divided into two
kinds: passive and active.
Passive transport
Passive transport only achieves net movement of solutes
across a membrane when the movement is from a higher
concentration to a lower concentration. Thus, passive
transport means an approach to a chemical equilibrium.
Passive transport cannot move solutes across a membrane
from a lower concentration to a higher concentration.
Passive transport can be simple diusion of small
molecules across a bilayer. Since lipid bilayers are relatively
impermeable to any solutes, this normally occurs very
slowly and is observed only when the solutes are small
molecules. Because the interior of the lipid bilayer is
hydrophobic, it is thermodynamically unfavourable for
water-soluble solutes to enter the bilayer interior, and thus
passage of water-soluble solutes through the membrane is
characterized by a relatively low probablility. For example,
glucose can diuse only slowly across a lipid bilayer. The
larger molecule of sucrose will diuse so much more slowly
that lipid bilayers are often considered to be impermeable
to sucrose. Lipid bilayers are also relatively impermeable
to charged solutes, like sodium ions, because of the
unfavourable free energy cost of introducing a charged
species into the bilayer interior.
Passive transport in biological membranes is more
importantly observed as facilitated diusion. Facilitated
diusion depends upon integral membrane proteins to
oer an alternative pathway across a membrane for a polar
solute that overcomes the thermodynamic barrier of
introducing a water-soluble solute into the hydrophobic
interior of the lipid bilayer. One way in which this can be
achieved is for the protein to exhibit as part of its threedimensional structure a polar channel suitable, or even
specic, for the solute of interest. The glucose transporter
of mammalian cells is an example of a transmembrane
protein that provides a pathway for facilitated diusion of
glucose across the plasma membrane. The potassium
channel is another example in which the protein creates a
channel lined with polar carbonyls suitable for potassium
to sequentially bind (to a series of sites) and pass through.
In each case, the solute transported moves down a
concentration gradient, to a compartment of lower
concentration.
Active transport
Active transport is distinguished from passive transport by
the utilization of cellular energy to support the transport of
solutes across a membrane, often against a concentration
gradient, or from a compartment of lower concentration to
a compartment of higher concentration. Cellular energy in
the form of ATP is often used for this purpose. For
example, the transport of sodium ions out of a cell (to keep
the cytoplasmic concentration of sodium low) requires the
pumping of sodium ions across the plasma membrane to
the outside of the cell where the sodium concentration is
higher than inside the cell. This transport is achieved by
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Signal transduction
Regulation of biological function at the cellular level is
essential to normal function of any organism. Because of
the barrier function exhibited by the plasma membrane,
special mechanisms are required to communicate changes
in the extracellular environment to the interior of the cell.
Regulation of cell behaviour by hormones or other signals
from the outside of the cell is achieved through signal
transduction employing receptors (transmembrane proteins) in the plasma membrane of the cell. Binding of a
ligand to the extracellular face of this transmembrane
protein can alter its conformation, including that of the
intracellular face of the protein. Such a change in
conformation acts as a signal inside the cell. Either some
function is expressed directly by this conformational
change, or a cascade of intracellular events is initiated,
often mediated by a series of cytoplasmic proteins. An
example of the former can be found in the acetylcholine
receptor. Binding of acetylcholine (from the presynaptic
membrane) to the external part of this transmembrane
protein leads to a conformational change that results in the
opening of a sodium channel, allowing passive diusion of
sodium ions across the membrane and changing the
transmembrane electrical potential in the postsynaptic
membrane. An example of the latter is the response of a G
protein-coupled receptor such as the visual pigment
rhodopsin in the retinal rod cell, which can absorb a
photon of light. The light is absorbed by retinal which
undergoes a photoisomerization from 11-cis to all-trans
retinal and induces a conformational change in this
transmembrane protein. The cytoplasmic face of the
Enzymatic activity
A variety of enzymatic activities are membrane-bound.
These activities can be exhibited by any of the classes of
membrane proteins described above. Enzyme activities
may be intimately associated with some of the other
membrane functions described above. An example is active
membrane transport. ATP may be hydrolysed to provide
the energy necessary to support the movement of solutes up
a concentration gradient (from a lower concentration to a
higher concentration). Alternatively, membrane-bound
enzymes may take advantage of the orientation and
localization that membranes oer to facilitate enzymatic
activity. Cytochrome b5 must interact with cytochrome-b5
reductase to transfer electrons as part of the lipid
desaturase system. Their localization in the membrane
allows them to diuse laterally and encounter each other
for the necessary electron transfer.
Another example of membrane-bound enzyme activity
is the ATP synthetase system of the inner mitochrondrial
membrane. This protein complex can exploit the energy of
a transmembrane gradient of protons to synthesize ATP, a
highly integrated membrane function.
cell against concentration gradients by linking this transport to the hydrolysis of ATP. This particular transport
system is so important that it is the single greatest
consumer of cellular ATP in many cells.
ATP can be made through glycolysis, which utilizes, in
part, glucose transported across the plasma membrane by a
passive transport system. The glucose transporter of many
cells is a transmembrane protein that forms a channel for
the passage of glucose from the blood to the cytoplasm of
the cell where it can be metabolized by the enzymes of the
glycolytic pathway. This transporter is under the control of
the insulin receptor. Activation of the insulin receptor, a
transmembrane protein of the plasma membrane, by
binding of insulin on the receptor face outside the cell
can lead to the recruitment of additional glucose transporters to the plasma membrane. The increase in number
of transporters increases the ux of glucose into the cell.
The b-adrenergic receptor, another transmembrane
protein in the plasma membrane of some cells, upon
binding its ligand, adrenaline, will change its conformation
and activate the corresponding G protein in the cytoplasm.
This G protein, in turn, activates adenylate cyclase,
increasing the production of cAMP, an intracellular
second messenger. This cascade of events leads to a
signicant change in cellular metabolism.
Receptor-mediated endocytosis is another function of
the plasma membrane. Some receptors, upon binding their
ligand, cluster into coated pits, specialized regions of the
plasma membrane coated on the cytoplasmic face with a
protein called clathrin. This clathrin can mediate the
formation of a vesicle from that portion of the plasma
membrane that separates from the plasma membrane and
becomes an intracellular vesicle. This process will take
extracellular material into the cell, such as the ligated
receptor.
The surface of mammalian cells is covered with complex
carbohydrate called the glycocalyx. Some of this carbohydrate is provided by glycoproteins and glycolipids of the
plasma membrane. The glycocalyx may provide a protective coat to the cell, but these carbohydrate structures also
form the basis of some cell recognition systems. For
example, blood type is determined in part by glycoproteins
on the surface of human erythrocytes, as is cell adhesion in
blood clotting, and spermegg interactions. The cell coat
of carbohydrate interacts with external matrix and is
involved in cell motility.
The plasma membrane of many cells is lined on the inside
with a network of proteins forming a membrane skeleton
associated with the cytoplasmic face of the plasma
membrane. In the erythrocyte, this membrane skeleton
gives the cell its characteristic shape. Membrane skeletons
can connect with cytoskeletal networks. These networks in
turn can connect through the plasma membrane to other
cells such as at desmosomes.
These few examples will serve to illustrate the complex
functionality of the plasma membrane of mammalian cells.
Endoplasmic reticulum
The endoplasmic reticulum is an intracellular organelle
bounded by membranes with a mass ratio of lipid to
protein similar to that in the plasma membrane. The
endoplasmic reticulum functions as a factory for the
biosynthesis of membrane lipids and membrane proteins,
as well as proteins to be secreted. The early steps of
synthesis of the lipids utilize soluble enzymes, but the later
steps all use membrane-bound enzymes because of the
hydrophobic nature of the lipid. Integral membrane
proteins are made on the endoplasmic reticulum in a
concerted process involving membrane-bound ribosomes.
Synthesis of the integral membrane protein proceeds in
concert with folding and insertion of the hydrophobic
portions of the membrane proteins into the protein.
Proteins to be secreted are also synthesized on ribosomes
bound to the endoplasmic reticulum membrane, and the
synthesis process occurs in concert with the transport of the
protein into the lumen of this organelle. Early stages of
protein glycosylation also occur in the endoplasmic
reticulum, mostly on asparagines (N-linked glycosylation)
in eukaryotes (not in prokaryotes). Core carbohydrate
structures are synthesized in the endoplasmic reticulum
membrane on dolichol, a hydrophobic isoprenoid, and are
transferred to the newly synthesized protein. This synthesis
of precurser carbohydrate structures undergoes some
processing and further maturation eventually in the Golgi.
A specialized machinery for intracellular transport
orgininates in the endoplasmic reticulum. Transport of
newly synthesized membrane components, and proteins to
be secreted, to the Golgi and other intracellular targets is
achieved by membrane-bounded vesicles. These vesicles
pinch o from the endoplasmic reticulum in a regulated
process that sorts materials to be transported from native
endoplasmic reticulum proteins involved in protein and
lipid synthesis, which are not transported. The process of
vesicular transport is energy-dependent and utilizes a
complex protein machinery.
A fundamental process called membrane fusion is
involved. Membrane fusion initially occurs when a vesicle
forms from the endoplasmic reticulum in preparation for
transport to the Golgi. One membrane separates into two.
When the vesicle arrives at the Golgi, another membrane
fusion process occurs as the vesicle membrane becomes one
with the Golgi membrane. These fusion processes preserve
the integrity of the lumen such that the lumen of the
endoplasmic reticulum is in a sense common with the
lumen of the Golgi.
Golgi
The Golgi is actually a series of stacked organelles that are
in communication with each other through the vesicle
transport system described above. Extensive posttranslational modication of proteins occurs in the Golgi.
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Endosomes
A specialized set of intracellular organelles receive
materials taken up by the cell through receptor-mediated
endocytosis. In these organelles, sorting of components of
the coated vesicles can occur. Sometimes the receptor is
recycled to the plasma membrane, while the ligands may be
used within the cell. Some components are shunted to the
lysosome for degradation.
Nuclear membrane
The nuclear envelope is a double membrane system that
surrounds the nucleus. The inner membrane is continuous
with, but compositionally distinct from, the outer nuclear
membrane which resembles the endoplasmic reticulum
including ribosomal protein synthesis. This membrane
system is involved in regulation of gene expression and
mRNA processing. Connecting the two membranes are the
nuclear pores, large complexes of protein that form pores
through which solutes and small proteins can pass between
the nucleus and cytoplasm. For example, these pores
actively transport subunits of DNA polymerase from the
site of synthesis in the cytoplasm to the nucleus, regulated
by nuclear localization signals in the amino acid sequence.
Processed RNA is actively transported from the nucleus to
the cytoplasm through the nuclear pores.
Mitochondrial membranes
Mitochondria are constructed of a double membrane
system. Mitochondria are the primary sites of production
of ATP, the common energy currency of the cell. Oxidative
phosphorylation takes place in mitochondria through
complexes of proteins in the inner mitochondrial membrane, very similar to oxidative phosphorylation in
bacteria. ATP synthesis is achieved using the energy of
the proton gradient across the inner mitochondrial
membrane. This membrane has a specialized lipid composition. In particular, diphosphatidylglycerol, or cardiolipin, is exclusively found in the mitochondria. The inner
mitochondrial membrane is very low in sterol content and
is very high in protein content. Accordingly, the mass ratio
Bacterial membranes
Virus membranes
Further Reading
Alberts B, Gray D, Lewis J, Ra M, Roberts K and Watson J (1994) The
Molecular Biology of the Cell. New York: Garland Press.
Vance DE and Vance J (1996) Biochemistry of Lipids, Lipoproteins, and
Membranes. Amsterdam: Elsevier.
Yeagle PL (1993) The Membranes of Cells, 2nd edn. San Diego:
Academic Press.