Eighth Literature
Membrane Structure and Function
Life, as we know it, depends on a fragile lipid membrane
that separates each cell from the surrounding world. These
membranes, composed of two layers of lipids, are generally
impermeable to ions and macromolecules. Proteins embedded in the
lipid membrane facilitate the movement of ions, allowing cells to
create an internal environment different from that outside.
Membranes also subdivide the cytoplasm of eukaryotic cells into
compartments called organelles. Chapter 7 introduces the features
that are shared by all biological membranes: a bilayer of lipids,
integral proteins that cross the bilayer, and peripheral proteins
associated with the surfaces.
Membranes are a planar sandwich of two layers of lipids that
act as two-dimensional fluids. Each lipid has a polar group from
which extend hydrocarbon tails that are insoluble in water. The
hydrocarbon tails are in the middle of the membrane bilayer with
polar head groups exposed to water on both surfaces. In spite of the
rapid, lateral diffusion of these lipids in the plane of the membrane,
the hydrophobic interior of the bilayer is poorly permeable to ions
and macromolecules. This impermeability makes it possible for
cellular membranes to form barriers between the external
environment, cytoplasm, and organelles. The selectively permeable
membrane around each organelle allows the creation of a unique
interior space for specialized biochemical reactions that contribute to
the life process. Chapters 18 to 23 consider in detail all of the
organelles, including mitochondria, chloroplasts, peroxisomes,
endoplasmic reticulum, Golgi apparatus, lysosomes, and the vesicles
of the secretory pathway.
Peripheral membrane proteins that are found on the surfaces of
the bilayer often participate in enzyme and signaling reactions.
Others form a membrane skeleton on the cytoplasmic surface that
reinforces the fragile lipid bilayer and attaches it to cytoskeletal
filaments.
Integral membrane proteins that cross lipid bilayers feature
prominently in all aspects of cell biology. Some are enzymes that
synthesize lipids for biological membranes (see Chapter 20). Others
serve as adhesion proteins that allow cells to interact with each other
or extracellular substrates (see Chapter 30). Cells need to sense
hormones and many other molecules that cannot penetrate a lipid
bilayer. Therefore, they have evolved thousands of protein receptors
that span the lipid bilayer (see Chapter 24). Hormones or other
extracellular signaling molecules bind selectively to receptors
exposed on the cell surface. The energy from binding is used to
transmit a signal across the membrane and turn on biochemical
reactions in the cytoplasm
A large fraction of the energy that is consumed by organs such
as our brains is used to create ion gradients across membranes.
Several large families of integral membrane proteins control the
movement of ions and other solutes across membranes. Chapter 8
introduces three families of pumps that use adenosine triphosphate
(ATP) hydrolysis as the source of energy to transport ions or solutes
up concentration gradients across membranes. For example, pumps
in the plasma membranes of animal cells use ATP hydrolysis to expel
Na+ and concentrate K+ in the cytoplasm. Another type of pump
creates the acid environment inside lysosomes. A related pump in
mitochondria runs backward, taking advantage of a proton gradient
across the membrane to synthesize ATP. A third family, called ABC
transporters, use ATP hydrolysis to move a wide variety of solutes
across plasma membranes.
Carrier proteins (Chapter 9) facilitate the movement of ions and
nutrients across membranes, allowing them to move down
concentration gradients much faster than they can penetrate the lipid
bilayer. Some carriers couple movement of an ion such as Na + down
its concentration gradient to the movement of a solute such as glucose
up a concentration gradient into the cell. Carriers generally change
their shape reversibly to transport their cargo across the membrane
one molecule at a time.
Channels are transmembrane proteins with selective pores that
allow ions, water, glycerol, or ammonia to move very rapidly down
concentration gradients across membranes. Taking advantage of ion
gradients created by pumps and carriers, cells selectively open ion
channels to create electrical potentials across the plasma membrane
and some organelle membranes. Many channels open and close their
pores in response to local conditions. The electrical potential across
the membrane regulates voltage-gated cation channels. Binding of a
chemical ligand opens other channels. For instance, nerve cells
secrete small organic ions (called neurotransmitters) to stimulate
other nerve cells and muscles by binding to an extracellular domain
of cation channels. The bound neurotransmitter opens the pore in the
channel. In the cytoplasm, other organic ions and Ca2+ can also
regulate channels. Cyclic nucleotides open plasma membrane
channels in cells that respond to light and aromas. Inositol
triphosphate and Ca2+ control channels that release Ca2+ from the
endoplasmic reticulum.
All living organisms depend on combinations of pumps, carriers,
and channels for many physiological functions Cells use ion
concentration gradients produced by pumps as a source of potential
energy to drive the uptake of nutrients through plasma membrane
carriers. Epithelial cells lining our intestines combine different
carriers and channels in their plasma membranes to transport
sugars, amino acids , and other nutrients from the lumen of the gut
into the blood. Many organelles use carriers driven by ion gradients
for transport. Most cells use ion channels and transmembrane ion
gradients to create an electrical potential across their plasma
membranes. Nerve and muscle cells create fast-moving fluctuations
in the plasma membrane potential for high-speed communication;
operating on a millisecond time scale, voltage-gated ion channels
produce waves of membrane depolarization and repolarization called
action potentials.
Our abilities to perceive our environment, think, and move
depend on transmission of electrical impulses between nerve cells and
between nerves and muscles at specialized structures called synapses.
When an action potential arrives at a synapse, voltage-gated Ca2+
channels trigger the secretion of neurotransmitters. In less than a
millisecond, the neurotransmitter stimulates ligand-gated cation
channels to depolarize the plasma membrane of the receiving cell.
Muscle cells respond with an action potential that sets off
contraction. Nerve cells in the central nervous system integrate
inputs from many synapses before producing an action potential.
Pumps and carriers cooperate to reset conditions after each round of
synaptic transmission.
Composition of Biological Membranes
Biological membranes are composed of phospholipids,
glycolipids and cholesterol. Membrane lipids are linked together
through the cooperative effects of multiple weak noncovalent
interactions such as van der Waals forces and hydrogen bonds,and as
a result there is considerable fluidity of movement within the
membrane—the constituents are free to diffuse laterally and
rotationally. The overall structure is that of a fluid of lipids and
membrane associated proteins undergoing Brownian motion.The
motions of the molecules
are not completely unrestricted, but instead are limited to specific
regions of the membrane, giving rise to a mosaic of membrane
compartments.
Three classes of lipids are found in biological membranes—
phospholipids, glycolipids, and cholesterol. Phospholipids are the
primary constituents.
1 . Phosphoglycerides
contain a glycerol backbone that is linked to a phosphoryl group
bonded to a phosphorylated alcohol group. A different backbone
component, sphingosine, is used in the sphingolipids. Of the four
commonly occurring phospholipids, all except phosphatidylserine
have uncharged head groups.
Phosphatidylserine has a negatively charged head group and is found
exclusively in the cytoplasmic leaflet. Phosphatidylinositol is of
special importance in metazoans. It is reversibly phosphorylated at
one or more OH sites on the inositol ring by lipid kinases to generate
lipid signal molecules that coordinate a number of cellular processes
including cytoskeleton control and motility, insulin signaling (glucose
and lipid metabolism), and growth factor-promoted cell survival.
2. The Glycolipids:
Like the phospholipids, have a backbone connected to fatty acyl
chains. They differ from the phospholipids in that they contain one
or more sugar groups in place of the phosphoryl-alcohol bearing
head group of the phospholipids .Glycolipids are found in the
exoplasmic leaflet of the plasma membrane, and are believed to
promote cell-to-cell recognition. The sugar residues that form the
hydrophilic head extend out from the cell surface.
Lipid constituents of the plasma membrane:
Exoplasmic—Outer;
Cytoplasmic—Inner.
*Phospholipids Phosphatidylcholine (PC): Exoplasmic leaflet
*Phosphatidylethanolamine: Cytoplasmic leaflet
*Phosphatidylserine :Cytoplasmic leaflet, negatively charged head,
Sphingomyelin group
*Phosphatidylinositol :Exoplasmic leaflet, sphingosine backbone,
Major role in signaling
*Glycolipids Exoplasmic leaflet, cell-to-cell recognition
*Cholesterol Influences fluidity and membrane organization
* Microdomains and Caveolae in Membranes
Biological membranes contain microdomains and caveolae
specialized for signal transduction. Lipids found in biological
membranes vary in chain length and degree of saturation. Chains
vary in length, having an even number of carbons typically between
14 and 24, with 16, 18, and 20 most common in phospholipids and
glycolipids. Chains with one or more double bonds are unsaturated.
These bonds are rigid and introduce kinks in the chain. In a fully
saturated acyl chain the carbon-carbon atoms are covalently linked
by single bonds. Each carbon atom in such a chain can establish a
maximum possible number of bonds with hydrogen atoms, hence the
term “saturated.” Such chains are free to rotate about their carboncarbon bonds, and can be packed tightly. In contrast, the kinks
present in an array of unsaturated lipids cause irregularities or voids
to appear in the array; these molecules cannot be packed as tightly.
The degree of saturation of the acyl chains and the cholesterol
content influence the melting point and fluidity of the lipids in the
membrane. This point can be illustrated by some everyday examples.
Fats, oils, and waxes are examples of lipids. Butter, a saturated lipid,
is a solid gel at room temperature, while corn oil, an unsaturated
lipid, is a liquid at the same temperature. Cholesterol plays an
important role in determining the fluidity of the membrane
compartments. It is smaller than the phospho- and glycolipids and is
distributed between both leaflets. As the concentration of cholesterol
increases, the lipid membrane becomes less disordered, gel-like and
more like an ordered liquid in which the lipids are more tightly
packed together, especially when saturated sphingolipids are present
.
Microdomains and Caveolae in Membranes
Schematic representations of phospho- and glycolipids and
cholesterol:
(a) A phospholipid such as PC consisting of a pair of acyl chains in
the tail region, a backbone, which in this case is glycerol, and a head
region consisting of a phosphoryl group
plus an alcohol group
(b) A phosphatidylinositol molecule consisting of a tail region, a
glycerol backbone, and a phosphoryl group coupled to a hexagonal
inositol ring in the head region.
(c) A glycolipid in which the head group consists of one or more
sugar groups .
(d) A cholesterol molecule is composed of a fatty acyl tail connected
to a rigid steroid ring assembly with an OH group at the terminus
that serves as its polar head.
The plasma membranes of eukaryotes are not uniform, but rather
contain several kinds of lipid domains, each varying somewhat in its
lipid composition.
Compartments enriched in cholesterol and/or sphingolipids
contain high concentrations of signaling molecules: GPI-anchored
proteins in their exoplasmic leaflet and a variety of anchored proteins
in their cytoplasmic leaflet. Two kinds of compartments—caveolae
and lipid rafts—enriched in cholesterol and glycosphingolipids, are
specialized for signaling.
Caveolae (little caves) are detergent-insoluble membrane domains
enriched in glycosphingolipids, cholesterol, and lipid-anchored
proteins. Caveolae are tiny flask-shaped invaginations in the outer
leaflet of the plasma membrane. They play an important role in
signaling as well as in transport. Caveolae may be flat, vesicular, or
even tubular in shape, and may be either open or closed off from the
cell surface.They are detergent insoluble and are enriched in coatlike
materials, caveolins, which bind to cholesterol.
Cholesterol- and sphingolipid-enriched microdomains can
float within the more diffuse lipid bilayer. The second kind of
cholesterol- and sphingolipid-enriched compartment is a lipid raft. It
does not have a cave-like shape and does not contain caveolins, but
instead is rather flat in shape. The fluid and detergent-insoluble
properties of both the rafts and the caveolae arise from the tight
packing of the acyl chains of the sphingolipids and from the high
cholesterol content. The cholesterol molecules not only rigidify the
compartment but
Organization of Signal
Calcium, & Cyclic AMP
Complexes
by
Lipids,
Lipids and the lipid bilayer:
(a) Membrane bilayers contain a mixture of amphipathic lipids. Each
lipid molecule has a hydrophilic (polar) head region and a twopronged hydrophobic tail region oriented as shown.Tails are fatty
acyl chains, hydrocarbon chains with a carboxylic acid (COOH)
group at one end and (usually) a methane group at the other
terminus. In cells, the polar head of each lipid moleculeis surrounded
by water molecules and thus is hydrated. The density of water
molecules drops off rapidly in the hydrophobic interior.
(b) Small cholesterol molecules are situated in between the larger
lipid molecules. Lipids differ from one another in the number, length,
and degree of saturation of the acyl chains, and in the composition of
their head groups. The overall packing density is greater in (b)
than in (a) due to the presence of cholesterol and of lipids with
straighter saturated acyl chains. Signaling proteins carrying a GPI
anchor attach to the exoplasmic leaflet while signaling proteins
bearing acetyl and other kinds of anchors attach to the cytoplasmic
leaflet. These proteins congregate in cholesterol and sphingolipidenriched membrane compartments. Also facilitate the formation of
signaling complexes and the initiation of signaling by them.
Lipid Kinases Phosphorylate Plasma Membrane
Phosphoglycerides
The
plasma
membrane
phosphoglyceride
known
as
phosphatidylinositol plays an important role in signaling,
cytoskeleton regulation, and membrane trafficking. The inositol ring
of the phosphatidylinositol molecule contains
a phosphoryl group at position 1 that is tied to the glycerol backbone.
All other OH groups of the inositol ring can be phosplorylated except
those at positions 2 and 6. Just as protein kinases catalyze the
transfer of phosphoryl groups to selected amino acid residues, lipid
kinases catalyze the transfer of phosphoryl groups to specific sites on
lipids. Several lipid kinases catalyze the phosphorylation of
phosphatidylinositol.
The lipid kinase phosphoinositide-3-OH kinase (PI3K) catalyzes the
transfer of a phosphoryl group from an ATP molecule to the OH
group at position 3 of the inositol ring of the lipid. Other lipid
kinases, PI4K and PI5K, catalyze the transfer of phosphoryl groups
to the other available sites, positions 4 and 5, on the ring. An entire
ensemble of phosphoinositides can be produced through the addition
and subtraction of phosploryl groups from positions 3, 4, and 5 of the
inositol rings.