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Last Update: 2 November 2017 Part I

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Fluid Mosaic Model of the Cell Membrane
Q: Define plasma membrane. What are the characteristics feature of the plasma membrane?
Describe the Fluid Mosaic Model of the plasma membrane. Describe the factors, which is altered
the membrane fluidity? Phospholipid molecule are also distributed asymmetrically in the
plasma membrane - Justify the statement. Add a short note on freeze fracture microscopy.

Definition
Exceedingly thin, elastic, selectively permeable, lipoproteinous, quasifluid living limiting
membrane called biomembrane, cytoplasmic membrane, plasma membrane or cell membrane,
bound outer surface of all protoplast.
In broad sense, the term cell membrane also includes the limiting membranes of cell
organelles like mitochondria and lysosomes and other membranes like those of the nuclear
envelop, the endoplasmic reticulum and Golgi complex. These membranes, however, resemble
the plasmalema in having no cell cement.

Characteristic feature of the Plasma membrane

Highly diverse in structure and function.

Doses not constitute a very inert barrier between the protoplasm and environment.
Sheet like structure, which forms a closed boundary of cell and gives individuality and
integrity.
The membrane has an unique self-Sealing properties and thus always formed an
compacted closed boundary and control the cellular mileu-interia (intra cellular
environment).
Thickness of the cell membrane very from 16 100
Membrane composed of lipids and proteins and their ration may ranges from 4:11:4
It has carbohydrate, vitamins, enzymes etc.
Lipids of the membrane are small molecule, which have hydrophobic and hydrophilic
moieties Amphipathic molecule. When it set free in aquas solution and sonicate it (lipid)
then instantly form closed boundary-Called Micelle.
Membrane proteins are as compared to icebergs floating in the sea of the phospholipid
bilayer and perform either of enzymatic activity, cellular communications or architectural
support.
The membrane protein forms specific gates channels, receptors and its permeability is
highly selective in nature. Such selective permeability permits the selective uptake of the
solvent, solutes and particles. Specific channels through which ions enters out side to
inside or vice versa and thus maintain the ionic balance.
Specific bonds involved between the lipids and proteins and it is non-covalent in nature.
Membrane are highly asymmetrical, the overall distribution of the lipid and proteins is
random.
Cell membrane is not a solid structure. It is neither solid nor liquid but is quasifluid in nature.
Due to dynamic, the protein molecules can move freely in the liquid-sea of the lipid bilayer.

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The cell and most organelles are individually surrounded by their own thin envelope. The envelope
surrounding the entire cell is called the plasma membrane. According to the fluid mosaic model,
all membranes are composed of a double layer of lipid molecules, called the lipid bilayer, in which
proteins are embedded (Fig. 1). The lipid bilayer acts as a barrier to the diffusion of polar solutes,
whereas the embedded proteins provide the pathways for

1. the selective transfer of certain molecular substances through the lipid barrier, and

2. the mechanical transfer of information from the ECM into the interior of the cell.

The plasma membrane

actually represents only a
tiny fraction of the total
membrane surface in the
cell. For example, the
combined membrane
surface area of the
endoplasmic reticulum is 44 times larger than the
plasma membrane surface area for a typical human
cell.

FIGURE 1. General models for membrane

structure.
a, The SingerNicholson 'fluid mosaic model' (ref. 1). b,
An amended and updated version. Source: Donald M.
Engelman, Nature 438, 578-580 (1 December 2005),
nature 04394

Lipid bilayer plasma membranes are 6-10 nm thick.

The major membrane lipids are phospholipids, fatty acid chains
in the range of 16-18 carbons long; chains with fewer than 12
carbons cannot form a stable bilayer. Phospholipid chains are
amphipathic molecules -- one end, the head, has a negatively-
charged (polar) region, while the remainder of the molecule, the
tail, consists of two (nonpolar) long fatty acid chains. The
phospholipids in cell membranes self-organize into a
bimolecular layer, with the nonpolar fatty acid chains in the
middle. The polar regions are oriented toward the membrane
surfaces due to their attraction to the polar water molecules in
the extracellular and cytosolic fluids.

The plasma membrane also contains other lipids (Table 8.18). For example, cholesterol, a
steroid lipid, acts as a "mortar" that fills in small gaps in the phospholipid structure, thus improving
membrane impermeability to small water-soluble molecules like glucose by a factor of ten.
Cholesterol also acts as a membrane antifreeze agent, decreasing bilayer fluidity at higher
temperatures (e.g., raising lipid bilayer "melting point") and preventing hydrocarbon chains of
phospholipids from aggregating at lower temperatures (e.g., lowering membrane "freezing point").
Plasma membranes may contain up to ~1 cholesterol molecule for each phospholipid molecule.
The precise lipid composition of plasma membranes varies from one cell type to another, and also
varies among the membranes of organelles within each cell type (Table 8.18). Medical nanorobots
equipped with suitable chemosensors may access this information, both for cell type identification
during extracellular navigation and for organelle type identification during intracellular navigation.
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There are ~5 x 106 lipid molecules in a 1 micron2 area of lipid bilayer or ~2.5 bilayer lipid pairs/nm2
of cell membrane surface. Thus the plasma membrane of a typical 20-micron human tissue cell
contains ~10 billion lipid molecules. Phospholipids are not covalently bound to each other, so each
lipid molecule is free to move independently, resulting in considerable random lateral
movement parallel to the bilayer surfaces. The long fatty acid chains each include one unsaturated
bond, producing a kink in the otherwise straight chain that prevents close packing (and
solidification). The chains also wiggle back and forth, so the lipid bilayer has fluidlike
characteristics much like a layer of oil on a water surface. Movement of hydrophilic head groups
through the hydrophobic interior of the membrane is thermodynamically unfavorable. Such flip-
flopping, or transverse diffusion, does occur in membrane lipids but is relatively slow. For instance,
a typical phospholipid molecule undergoes transverse diffusion (one flip flop between monolayers)
once every several hours in a lipid bilayer. By contrast, lateral diffusion of phospholipids
(movement within each monolayer) is so rapid that a lipid molecule can move 10 microns (the
equivalent of ~12% of cell circumference) in a few seconds.

Lipids and many membrane proteins diffuse rapidly in the plane of the membrane
Biological membranes are not rigid structure but it is high dynamic in nature. On the contrary, lipids
and many membrane proteins are randomly shows in lateral motion.
Membrane protein movement
Many membrane protein move through the plane of membrane which are visualised under
fluorescence microscopy. It can be observed by the different fluorescence labelling of the two cell (human +
mouse), and observed subsequently after somatic hybridisation of these cell. Such experiment re-valued that
a membrane protein can diffused through a distance of several macrons in approximately one minute.

Membrane lipid movement

A more general and quantitative method for measuring the lateral mobility of membrane molecule
(lipids and proteins) in the intact cell is the fluorescence, photo bleaching recovery technique. This
technique revealed that spontaneous rotation of lipid from one face to the other is a very slow process in
contrast with their movement parallel to the plane of the bilayer.
Types of movement of the lipid molecule
The movement of the lipid molecule is considerably variable from time to time and these are -
1) Flexion: It is possible that there is a rapid internal motion involving flexing with in each lipid molecule.
(A)
2) Lateral diffusion: The diffusion of a molecule from one membrane surface at a plane is termed lateral
diffusion (B)
3) Transverse diffusion or Flip-flop: It is the transition of a molecule from one membrane surface to the
other is called transverse diffusion or flip-flop. (C). The cis-diffusion also have been reported. (C1)
4) Rotation: A lipid molecule might rotate about their own axis. (D)
In fact the flip-flop of the proteins molecules has not been observed. Hence membrane asymmetry can
be preserved for long periods.
The rapid movement of the lipids and proteins molecules are satisfied to the model of Singer &
Nicolson, because they considered the bio-membrane are highly fluid and high dynamic which always
shows like a movie picture of fluid mosaic model.

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 Lipids are distributed in an asymmetric manner in
membrane
In contrast to the random distribution of lipids between the
outer and inner lipid monolayers of liposome, there is an
asymmetric distribution of lipid components across biological
membranes. Each layer of the bilayer has a different composition
with respect to individual phosphoglycerides and sphingolipids. An
example is the asymmetric distribution of lipids in the human
erythrocyte membrane, as presented in Figure. Sphingomyelin is
predominantly in the outer layer, whereas phosphatidylethanolamine
is predominantly in the inner lipid layer. In contrast, cholesterol is
equally distributed on both sides of the plasma membrane. The
asymmetry of the lipids may be maintained by specific membrane
proteins that promote the transverse movement of specific lipids
from one side to the other. Recent studies suggest the involvement of metabolic energy in this process.
Uncatalysed transverse movement from one side to the other (i.e., flip-flop movement) of the
phosphoglycerides and sphingolipids is slow and is measured in days or weeks. The slow rate of transverse
movement is not unexpected, considering how unfavourable in thermodynamic terms it is to push or pull the
hydrophilic polar head group of a phospholipid through the hydrophobic interior of a membrane and then
reorient the group on the opposite side. The asymmetry of lipids in the erythrocyte membrane is an example
of how slow the transverse movement of membrane lipids is. Individual lipids can exchange with lipids in
the cell matrix, as well as with lipids of other membranes. Specific mechanisms to maintain both the
composition and asymmetry of lipids in membranes apparently exist.

Membrane proteins

Membrane proteins are embedded in the lipid bilayer plasma membrane. Indeed, it has been
said that the lipid bilayer serves as a "solvent" for membrane proteins. The plasma membrane
contains roughly equal masses of lipid and protein (Table 8.18). However, the mass of an
individual protein molecule is much larger than the mass of any lipid molecule, so there are 10-100
times more lipid molecules than protein molecules. The plasma membrane of a typical 20-micron
human tissue cell contains ~0.1 billion protein molecules.

There are two classes of membrane proteins: Integral (intrinsic) membrane proteins and peripheral
(extrinsic) membrane proteins.

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Integral membrane proteins are closely associated with membrane lipids and cannot be extracted
from the membrane without disrupting the lipid bilayer. Like phospholipids, integral proteins are
amphipathic. Polar amino acid side chains lie in one region of the molecule and nonpolar side
chains are in a separate region.
Thus integral proteins vertically
align with the amphipathic lipids in
the plasma membrane -- protein
polar regions position themselves at
the surfaces in association with
polar water molecules, while the
protein nonpolar regions are
attracted to the interior in
association with the nonpolar fatty
acid chains at the center of the lipid
bilayer membrane (Fig. 1). Many
integral proteins can move laterally
in the membrane; others are
immobilized by links to a network of
peripheral proteins located near the
cytoplasmic surface of the
membrane. How fast do embedded proteins laterally diffuse? If a single hybrid cell is created by
fusing two cells having radio chemically-tagged membrane protein molecules, ~1 hour is needed
for the two populations of transmembrane protein molecules to become thoroughly randomly
intermixed.

Most integral proteins are transmembrane proteins with polar regions at each end and a
nonpolar region in the middle, spanning the entire membrane. These polar regions may extend up
to 10-20 nm beyond the surface of the lipid bilayer, forming channels through which water, ions, or
chemical signals can pass into the cell. A few integral proteins do not cross the entire membrane
and are found only in the outer or inner layer, performing functions localized to only one
membrane surface. These proteins are also amphipathic and oriented parallel to the lipid
molecules. Some are anchored to the membrane by covalent bonds with phospholipids. For
example, in the red blood cell membrane, glycophorin spans the entire membrane, all glycolipids
and most of the phosphatidylcholine are in the outer monolayer, and the majority of the
phosphatidylethanolamine and phosphatidylserine molecules are in the inner monolayer
where most of the proteins reside. (Cholesterol is distributed about equally between the two
layers.) The number of different integral proteins in a membrane ranges from 6-8 in the
sarcoplasmic reticulum to over 100 in the plasma membrane (including enzymes, transport and
structural proteins, antigens and receptors), many of which are present in only a few copies per
cell, although the 135 micron2 red cell surface has ~1 x 106 copies of the glycophorin A molecule
and ~1 x 105 copies of glycophorin B.

Peripheral membrane proteins are bound to the hydrophilic regions of integral membrane
proteins or to the hydrophilic heads of membrane lipids by weak electrostatic forces. Most
peripheral proteins are located near the cytoplasmic surface of the plasma membrane rather than
on the extracellular surface and mediate such properties as cell shape and motility. Peripheral
proteins are not amphipathic and do not associate with the hydrophobic regions of the lipids in the
membrane interior.

Both lipid and protein components of the plasma membrane are continually removed and
replaced. Turnover allows the cell to continuously change out damaged components. This is a
highly selective process, since the rate of turnover varies for different proteins and lipids. For
instance, the half-life of some phospholipids in membranes is ~10,000 sec; the "off-rate" (half-life)
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for cholesterol from a lipid bilayer (e.g., the red cell surface) into the cytoplasm is ~7200 sec at 310
K. Protein turnover half-lives may range from several minutes to several years, but the "typical"
protein has a turnover half-life of ~200,000 sec or ~2 days. Protein replacement is carried out by
protease enzymes located in the cytoplasm and in lysosomes. Replacement rates also depend
upon cell type. For example, the plasma membrane surface of the macrophage has an unusually
fast mean turnover time, ~1800 sec, vs. ~5400 sec for fibroblasts.

The plasma membrane also contains small amounts of carbohydrate. This carbohydrate is
covalently linked to some of the membrane lipids and proteins. Carbohydrate portions of the
membrane glycoproteins are always located at the extracellular surface, forming the glycocalyx
(together with collagen proteins and glycosaminoglycans, aka "mucopolysaccharides"). The red
cell membrane, for instance, contains 52% protein, 40% lipid, and 8% carbohydrate by weight. A
small proportion of membrane carbohydrate is glycolipids, but most is in the form of glycoproteins.
The sugar units are usually short oligosaccharide chains attached to serine, threonine, or
asparagine side chains.

The glycocalyx, or fuzzy coat, lies exterior to the plasma membrane. In most cell types, the
glycocalyx is 10-100 nm thick consisting of tangled strands of up to ~10,000-atom glycoproteins
each measuring 5-8 nm thick and up to 100-200 nm in length. The experimentally-measured
thickness of the glycocalyx of various cells ranges from ~6 nm for human blood-group A
erythrocytes, to 13 nm in Eimeria microgametes, 20-30 nm for chick fibroblasts, 30-60 nm for
human bladder cells, 40-70 nm for human lymphocytes, ~50 nm for human myocardial cells, 56
nm for frog mesenteric micro vessels, >70 nm for rat vasculature, ~81 nm for rabbit endothelial
cells of the systemic arteries (e.g., carotid), and 90 nm for human cochlear hair cells. The most
prominent glycocalyx are found in intestinal epithelial cells, where the fuzzy coat may reach 150
nm in thickness and consists primarily of oligosaccharide chains 1.2-2.5 nm in diameter. (There is
one report of rat venule endothelial cells with glycocalyx up to 870 nm thick, and a few
macroscopic parasites such as the fork-tailed cercariae of the blood fluke Schistosoma mansomi
have glycocalyx 500-2000 nm thick.)

The glycoproteins of the glycocalyx provide a set of highly specific biological markers that are
readily recognizable by suitably equipped medical nanorobots. These markers assist normal
cellular interactions by allowing blood group recognition, bacterial and toxin binding sites, egg
recognition by sperm, immune responses, guidance of embryonic development, and cellular
lifespan determination (e.g., the red cell coat thins with age which may serve as an RBC removal
signal for phagocytes and in the liver).

The cell's surface is also strewn with numerous pits and indentations. For example, one class of
these is the "coated pits" whose inner surfaces are covered by a dense layer of the protein
clathrin, important in receptor-mediated endocytosis wherein proteins and other large molecules
are imported into the cytoplasm. Another class of membrane indentation is the ~50 nm caveolae
("tiny caves") that serve to draw substances such as vitamins and signal transduction molecules
into the cell's interior. Caveolae are coated with a unique membrane marker protein called
caveolin, making them easy for nanorobots to identify.

Fluidity of the Plasma Membrane

The interactions among the different lipids and between lipids and proteins are very complex and
dynamic. There is fluidity in the lipid portion of the membrane in which both the lipids and proteins move.
The degree of fluidity is dependent on the temperature and composition of the membrane.

1) Depends on temperature

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 At low temperatures, the lipids are in a gel-crystalline state, with the lipids restricted in their
mobility. As the temperature is increased, there is a phase transition into a liquid-crystalline state, with an
increase in fluidity. With liposomes prepared from a single pure phospholipid, the phase transition
temperature, Tm, is rather precise; but with liposomes prepared from a mixture of lipids, the Tm becomes
less precise because individual clusters of lipids may be in either the gel-crystalline or the liquid-crystalline
state. The Tm is not precise for biological membranes because of their heterogeneous chemical composition.
Interactions between lipids and proteins also lead to variations in the gel-liquid state throughout the
membrane and differences in fluidity in different areas of
the membrane.

2) Depends on chemical composition of the membrane

a. Depends on lipid structure variability
The specific composition of the individual
biological membranes leads to differences in fluidity.
Phosphoglycerides containing short-chain fatty acids will
increase the fluidity as does an increase in unsaturation of
the fatty acyl groups. The cis-double bond in an
unsaturated fatty acid of phospholipid leads to a kink in
the hydrocarbon chain, preventing the tight packing of
the chains, and creates pockets in the hydrophobic areas.
It is assumed that these spaces, which will also be mobile
due to the mobility of the hydrocarbon chains, are filled
with water molecules and small ions.
b. Depends on the Cholesterol
Cholesterol is a major determinant of the
membrane fluidity. Cholesterol with its flat stiff ring structure reduces the coiling of the fatty acid chain and
decreases fluidity. Too hydrophobic to form a sheet structure on its own. Cholesterol intercalates among the
phospholipids. Its polar hydroxyl group is in contact with the aquous solutions, near the polar head group of
the phospholipids, while the sterol rings interacts with and tends to immobilize the fatty acyl chains of the
phospholipids. The net effect of cholesterol on membrane fluidity varies, depending upon lipid composition.

Cholesterol restricts the random movement of the part of the fatty acid chain lying closest to the
outer surface of the bilayer. However, it separates and disperses the tail of the fatty acyl and causes the inner
regions of the bilayer to become slightly more fluid. However, cholesterol in high concentrations prevent to
fluidity

c. Depends on the Ca2+ ions

The Ca2+ ion directly decreases the fluidity of a number of membranes because of its interaction with
the negatively charged phospholipids, which reduces repulsion between the polar groups and increases the
packing of lipid molecules. This ion also causes aggregation of lipids into clusters, which reduces membrane
fluidity.

Fluidity at different levels within the membrane also varies.

The hydrocarbon chains of the lipids have a motion, which produces fluidity in the hydrophobic
core. The central area of the bilayer is occupied by the ends of the hydrocarbon chains and is more fluid than
the areas closer to the two surfaces, where there are more constraints due to the stiffer portions of the
hydrocarbon chains.
Cholesterol makes the membrane more rigid toward the periphery because it does not reach into the
central core of the membrane.
Individual lipids and proteins can move rapidly in a lateral motion along the surface of the
membrane. However, electrostatic interactions of polar head groups, hydrophobic interactions of cholesterol
with selected phospholipids or glycolipids, and protein-lipid interactions all lead to constraints on the
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movement. Thus, there may be lipid domains in which lipids move together, such as an island floating in a
sea of lipid. Movement of protein is slower than that of lipids and may be restricted by other membrane
proteins, matrix proteins, or cellular structural elements such as microtubules or microfilaments to which
they may be attached.
Evidence is accumulating that the fluidity of cellular membranes can change in response to changes
in diet or physiological state. Their content of fatty acid, and cholesterol is modified by a variety of factors.
In addition, pharmacological agents may have a direct effect on membrane fluidity. It is now
considered that some of the actions of anesthetics, which induce sleep and muscular relaxation, may be due
to their effect on membrane fluidity of specific cells. A number of structurally unrelated compounds induce
anesthesia, but their common feature is lipid solubility. Anesthetics increase membrane fluidity in vitro thus,
cellular membranes are in a constantly changing state, with not only movement of proteins and lipids
laterally on the membrane but with molecules moving into and out of the membrane.

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