Membrane structure

 Thin delicate structures, key function in cell’s most
important functions.
 Separates living cell from its enviornment.
 Selectively permiable barrier that allows transport of certain
substances and prevents transport of others.
 Provides frame work in which components can be
organized.
 Site where energy transduced from one form to the other.
 Contains receptors which bind specific ligands in the
external space and transfer information to cell’s interior
compartments.

 Bimolecular layer of amphipatic lipids (phospholipid
bilayer)
 2 segments with very different chemical properties.
 Polar heads (hydrophilic) face outside and non polar
hydrocarbon tails (hydrophobic) face inside.
 5-10nm thick.
 Contain phospholipids, proteins and steroid molecules.
 Structure called as “FLUID MOSAIC MODEL” and was
devised by S JONATHAN SINGER and GARATH NICHOLSON
of University of California in 1972.

 A membrane is a MOSAIC
 Proteins and other molecules are embedded in a
framework of phospholipids
 A membrane is FLUID
 Most protein and phospholipid molecules can move
laterally

 Compartmentalization
 Scaffold for biochemical activities
 Providing a selectively permeable membrane
 Transporting solutes
 Responding to external signals (signal
transduction)
 Intercellular interaction
 Energy transduction

 Impermeable barrier : passage of only selective
molecules like water and small hydrophilic molecules
 Stability : maintained by van der Waals and hydrophobic
interaction, although outer enviornments vary, bilayer has
strength to retain its characteristic architecture
 All phospholipid bilayer can spontaneously form
sealed closed compartments: separating the inside
enviornment from the external enviornment

Two surfaces of a cellular membrane:
 CYTOSOLIC FACE: faces the cytosol.
 EXOPLASMIC FACE: faces the exterior enviornment.
In the case of cellular membranes, exoplasmic face is
towards the interior and cytosolic face is towards the
exterior of the organelle. (Exeptions are mitochondria,
chloroplast and nucleous - ENDOSYMBIONT HYPOTHESIS)

 The ratio of lipid to protein in a membrane varies,
depending on type of cellular membrane, type of
organism and the type of cell.
 The components are:
a) Membrane lipids
b) Membrane proteins
c) Membrane carbohydrates
d) Membrane steriods

The plasma membrane contains three principal classes of
amphipathic lipids (contain both hydrophobic and hydrophillic
ends)
PHOSPHATE HEAD
(POLAR)
HYDROCARBON TAIL
(NON POLAR)

 Most abundant lipids.
 Derivatives of glycerol 3 phosphate.
 Contain a hydrophobic tail composed of 2 fatty acyl chains
esterified to the 2 hydroxyl group in glycerol phosphate
and a polar head attached to phosphate group (fatty acyl
chains can differ in number of carbon they contain and
degree of saturation)
 Classified according to nature of head group.
 Phosphatidyl choline contains a positively charged choline
head esterified to negatively charged phosphate.
 Plasmalogens contain 1 fatty acyl chain attached to C2 of
glycerol by ester linkage and 1 long hydrocarbon chain
attached to C1 of glycerol by ether linkage.

 At neutral pH, some phosphoglycerides contain no electric
charge (phosphatidyl choline) and some contain net negative
charge (phosphatidyl serine)
 Negatively charged phosphate group and hydroxyl group on
head groups interact strongly with water.

 Derived from amino alcohol Sphingosine.
 Long chain fatty acid attached by amide linkage to
sphingosine amino group.
 Have phosphate based polar head.
 Most abundant sphingolipid – Sphingomyelin- in which
phosphocholine is attached to terminal –OH group of
sphingosene.
 Sphingomyelins similar to phosphoglycerides and can form
mixed bilayers with them.
 Other sphingolipids are glycolipids.
 They constitute 2-10% of total lipid in plasma membrane.

 Depending on species and cell type carbohydrate concentration
varies from 2-10% by weight.
 More than 90% of membrane carbohydrate covalently linked to
proteins to form glycoprotein and rest to lipids to form
glycolipids.
 Carbohydrates of cell membrane face outside.

Carbohydrates of glycoproteins is present as short, branched
hydrophilic oligosaccharides.
Carbohydrate projections play an important role in mediating
the interactions of a cell with its enviornment and sorting of
membrane proteins to different cellular compartments,
Carbohydrates of the glycolipids of RBC plasma membrane
determine the blood type of a person.

 Consist of cholesterol and its analogues.
 Cholesterol is a 4 ring hydrocarbon.
 Although almostt entirely hydrocarbon, it is amphipathic
because its –OH group can interact with water.
 Abundant in mammalian cell, but absent in prokaryotes and
plant cells.
 About 50-90% of cholesterol in mammalian cells is present
in plasma membrane and associated vesicles.
 It is too hydrophobic to form bilayer by its own.
 The sterol must interact with phospholipid molecules to be
incorporated into biomolecules.
 Key function is its covalent addition to hedgehog protein, a
key signaling molecule in embryonic developement

 Thermal motion allows lipid molecules to rotate freely
around long axes and also to diffuse laterally within each
leaflet.
 Because movements are lateral, fatty acyl chains remain in
hydrophobic interior.
 A typical lipid molecule exchange places with its neighbors
in a leaflet about 10^7 times/sec and diffuse several
micrometers /sec at 37˚C.
 These diffusions indicate that viscosity of plasma membrane
is 100 times that of water- approx that of olive oil.
 A lipid molecule can diffuse the length of a bacteria is 1sec
and that of animal cell in 20secs.
 Movement observed by Fluorescence Recovery after
Photobleaching (FRAP) technique.

Fluorescence Recovery after Photobleaching (FRAP)
Fluorescence Recovery after photobleaching experiments can
quantify the lateral moovement of proteins and lipids within the
plasma membrane
Label
Bleach
With
laser
Fluoresce
nce
recovery
membrane
protein
Fluorescent
reagent
Bleached area
1 2 3

A technique by which two different type of cells can be fused
to produce one cell with common cytoplasm and continuous
plasma membrane.

 Cells are allowed to fuse with one another making the outer
surface of the cells sticky, so that their plasma membrane
adhere to one another.
 In 1970, Larry Frye and Michael Edidin conducted an
experiment where mice cell and human cell were allowed to
fuse and positions of specific proteins were followed once the
membrane had become continuous.
 To detect position, antibodies against both cells were prepared
and covalently linked to fluorescent dyes. Antibodies against
mice protein complexes to give green fluorescence and
antibodies against human proteins complexes to give red
fluorescence.
 The cells could be located under a fluorescence microscope.

At usual physiological
temperatures, hydrophobic
interior of natural membranes
generally has a lower viscocity
and fluid like consistancy

When fluid artificial
phospholipid membranes are
cooled below 37˚C, they
undergo phase transition from
fluid state to gel like state.

 Compromises between a completely rigid structure with no
mobility and a completely fluid non viscous liquid without
structural organisation and strength.
 Allows interactions to take place in membrane,
 Because of fluidity moleculles that interact can come together,
carryout necessary reactions, and move apart.
 Key role in membrane assembly.
 Many of cell’s basic functions, including cell movement, cell
growth, cell division, formation of intercellular junction,
secretions, and endocytosis, depend on the movement of
membrane components, which is achieved by fluidity.

 There are differences in relative abundance of phosphoglycerides and
sphingolipids between membranes in ER where phosphoglycerides are
synthesized and in golgi where sphingolipids are synthesized.
1. FLUIDITY
 Degree of bilayer fluidity depends on lipid composition, structure of
phospholipid bilayers and temperature.
 Saturated fatty acyl chains have greatest tendency to aggregate,
packing tightly together into a gel like state.
 Phospholipids with short fatty acyl chains have less surface area, less
van der Waal’s interaction and fluid consistancy.
 Cholesterol is important in maintaining appropriate fluidity of natural
membranes.

 Cholesterol is important in maintaining appropriate fluidity
of natural membranes.
 At low cholesterol concentration the steroid ring separates
and disperse phospholipid tails causing the inner regions of
membrane to be more fluid
 At concentrations present in plasma membrane, the steroid
rings interact with long hydrophobic tails of phospholipids
and tends to immobilize these lipids and decrease membrane
fluidity.

2. THICKNESS
Sphingomyelins associate into a more gel like and thick
bilayer than phospholipids.
Cholesterol increases membrane thickness.

3. CURVATURE
 Curvature of bilayer depends on lipid concentration.
 Depends on relative size of polar head and non polar tails of
phospholipids.
 Lipids with long tail and large head are cylindrical and
those with small head and long tail are conical.
 Result in formation oh highly curved membranes, such as
site of viral budding, microvilli, etc.

 Asymetry in lipid composition across bilayer.
 Although most phospholipids present in both leaflets.
 In the plasma membrane of human erythrocytes, sphingomyelin
and phosphatidyl choline are found in exoplasmic leaflet,
phosphatidyl ethanolamine, phosphatidyl serine and
phosphatidyl inositol form more fluid bilayer ; preferentially
located at cytosolic leaflet.
 This segregation influence bilayer curvature.
 Cholesterol is relatively evenly distributed.
 Phospholipases are enzymes that cleave various bonds in
hydrophilic ends of phospholipids.
 On addition to external medium, enzymes cannot penetrate
membrane and cleave off the head groups of only those lipids
present in the exoplasmic face.

 Membrane lipids are not randomly distributed.
 Lipids remaining after the extraction of plasma membrane
with non ionic detergent predominantly contain cholesterol
and sphingomyelin.
 These found in more ordered, less rigid bilayer; researchers
hypothesized that they form microdomains termed as lipid
rafts, surrounded by other more fluid phospholipids that are
extracted.
 Rafts can be destructed by methyl β cyclodextrin that
specifically extracts cholesterol out.

 By bringing many key proteins to proximity , these lipid
protein complex may facilitate signaling by cell surface
receptors and the subsiquent activation of cytosolic events.

 Defined by location within or at surface of the membrane.
 Proteins associated with particular membrane are responsible
for its distinctive function.
 Kind and amount of protein vary depending on subcellular
location and cell type.
eg: inter mitochondrial membrane contain 76% protein,
myelin membrane contain 18% protein.
 3 different types of protein:
a) INTEGRAL MEMBRANE PROTEIN
b) LIPID ANCHORED MEMBRANE PROTEIN
c) PERIPHERAL MEMBRANE PROTEIN

 AKA transmembrane proteins
 Span a lipid bilayer and comprises 3 segments.
 Cytosolic and exoplasmic face domains have hydrophillic
exterior surface that interact with aqueous solution on the
cytosolic and exoplasmic faces of the membrane.
 In contrast the membrane spanning segment contain more
hydrophobic aminoacids whose side chains protrude outward
and interact with the hydrophobic hydrocarbon core.
 Membrane spanning segment consist of 1 or more α helices or
multiple β strands.

 Technique for analyzing cell membrane structures.
 In this technique, tissue is frozen and struck with a knife
blade,which fractures the block into two pieces.
 Fracture plane often takes path between the two bilayers.
 Metals are deposited on exposed surface to form shadowed
replica and viewed under electron microscope.
 The fracture goes around the protein particle than cracking it
in half.
 Each protein separates with one half of the membrane leaving
a pit behind.

 Bound covalently to one or more lipid molecules.
 Hydrophobic segment embedded in one segment of the
membrane.
 Polypeptide chain itself does not enter phospholipid bilayer.

 Do not directly contact the hydrophobic core of phospholipid
bilayer.
 Bound to membrane indirectly by interactions with integral
or lipid anchored protein or directly to lipid head groups.
 Can be bound to either cytosolic or exoplasmic face of plasma
membrane.
 Cytoskeleton can be loosly associated with cytosolic face by
one or more peripheral proteins.
 Such interactions provide support for various cellular
membranes, helping to determine cell shape and much
properties, and 2 way communication between all exterior
and interior faces.

 α Helix dominate the transmembrane folded structures.
 Proteins containing α helix are stably embedded in membranes
because of energetically favorable hydrophobic and van der
Waal’s interaction of hydrophobic side chains in domains with
specific lipid and probably also by ionic interactions with the
polar head groups of phospholipids.
 A single α helical domain is sufficient to incorporate an
integral membrane protein into a membrane (membrane
embedded α helix made of continuos segment of hydrophobic
amino acid)
 Such an α helix is sufficient to span the hydrocarbon core of
the membrane.

3 proteins with α helical domain:
a) GLYCOPHORIN A
 Representative single pass transmembrane protein.
 One membrane spanning α helix.
 Transmembrane α helix of one glycophorin A polypeptide
associates with corresponding transmembrane helix of other
protein to form coiled coil dimer – common mechanism for
producing dimeric membrane protein and many membrane
protein form oligomers.

b) G PROTEIN COUPLED CELL SURFACE RECEPTOR
 Multipass transmembrane protein.
 Eg: bacteriorhodopsin

c) AQUAPORINS
 Family of highly conserved proteins that transport water,
glycerol and other hydrophilic molecules through plasma
membrane.
 Illustrates several aspects of structure of multipass
transmembrane system.
 Tetramers of 4 identical subunits.
 Each subunit has 6 membrane spanning α helices, some
transverse membrane at oblique angles.
 Has a long transmembrane helix with a bend in the middle,
2 α helix penetrating midway.

 Protein porin differ from other membrane by structure based
on α helix.
 Several type of porin present on outer membrane of Gram –ve
E.coli, mitochondria and chloroplast.
 Porins on outer membrane of E.coli enable passage of specific
type of disaccharide, other small molecule, as well as ions of
phosphate.
 Amino acid sequence of porins contain non of the long
hydrophobic segments of typical integral proteins.
 Porins are trimers of identical subunits, each subunit has 16 β
strands that form a sheet that twist into a barrel shaped
structure with a pore at centre.

 Porin has hydrophilic interior and hydrophobic exterior,
outward facing side groups on each of the β strands are
hydrophobic and form a nonpolar ribbon like band that
encircles the outside of the barel.
 Hydrophobic band interact with fatty acyl groups of membrane
lipids or with other porin monomers.
 Side groups facing inside – hydrophillic.

 Lipid anchored proteins are embedded in bilayer but the
protein itself does not enter the bilayer.
 One group of cytosolic proteins are anchored to cytosolic face
of membrane by fatty acyl group covalently attached to N
terminal glycine residue.
 Retension of such proteins at membrane by N terminal acyl
anchor is known as acylation.
 Second group of proteins are attached to a cystein residue at
or near C terminus.
 Some of these anchors are prenyl anchors built from 5C
isoprene units.

 Proteoglycans are anchored to exoplasmic face by 3rd type of
anchor group glycosylphosphatidylinositol. (GPI anchors)
 GPI anchors are glycolipids; they are both necessary and
sufficient for binding protein to the membrane

 Every type of transmembrane protein has an orientation
callesd as TOPOLOGY.
 Cytosolic segments face cytoplasm, exoplasmic segments face
opposite side of membrane.
 This assymetry confir different properties on the two
membrane.
 Membrane proteins are never been observed to flip-flop
across a membrane, which is energetically unfavourable.
 Membrane protein retain assymetric orientation in membrane
during membrane budding and fusion events.
 Same segment face cytosolic face and exoplasmic face.

 Assymetry maintained throughout lifetime of protein.
 Transmembrane glycoproteins are located so that
carbohydrate chains are in exoplasmic domain (proteins with
carbohydrate attached to serine, threonine, asparagine.)
 Glycolipids in which carbohydrate chain is attached to
glycerol or sphingosine are always located in exoplasmic
domains with carbohydrate chain protruding from membrane
surface.
 Both glycoproteins and glycolipids are abundant in plasma
membrane.
 As carbohydrate chains of both extend to extracellular space,
they interact with lectins, growth factors and antibodies.
 One of the consequences is ABO antigen interaction:

 Many water soluble enzymes use membrane phospholipids as
substrate and thus bind to membrane surfaces.
 Bind to polar head group of phospholipids and carryout
functions.
 Phospholipases hydrolyze various bonds in head groups of
phospholipids.
 Have important role in degradation and damage of old cell
membrane and are also active components in snake venom.

 Plasma membrane has dual function- to retain dissolved
contents of the cell and also to allow necessary exchange of
materials in and out of the membrane.
 Two means: passively by diffusion, or activly by an energy
coupled transport process.
 Two types of movement are;
a. PASSIVE TRANSPORT
b. ACTIVE TRANSPORT
MOVEMENT OF SUBSTANCES ACROSS CELL
MEMBRANE

 PASSIVE TRANSPORT:
Does not require the expenditure of energy.
a) DIFFUSION
b) OSMOSIS
c) FACILITATED TRANSPORT
i) ION CHANNELS
ii) FACILITATED DIFFUSION
 ACTIVE TRANSPORT:
energy coupled transport process.

 Spontaneous process
 Substance moves from its higher concentration to lower
concentration.
 Depends on random thermal motion of solutes.
 Exergonic process driven by an increase in entropy.
 If the substance is an electrolyte, the tendency to diffuse
depends on the ELECTROCHEMICAL GRADIENT.

 Movement of water molecules from a region of lower solute
concentration to a region of higher solute concentration
through a semipermeable membrane.
 Solution with higher solute concentration-hypertonic
 Solution with lower solute concentration-hypotonic
 Solutions with same solute concentration-isotonic
 In hypertonic solution cell shrinks
 In hypotonic solution cell swells
 In isotonic solution no change
 The sweling and shrinking of cells in slightly hypotonic and
hypertonic solution are temporary events.

 Lipid bilayer highly impermeable to small charged ions like
Na+, K+, Ca²+, Clˉ.
 In 1955 Alan Hodgkin and Richard Keyneys proposed that cell
membranes contain ion channels: openings in a membrane that
is specific for ions.
 But proof of such a channel was given by Bert Sakmann and
Erwin Neher of Max Planck University.
 They developed techniques to monitor ionic current passing
through a single channel.
 Accomplished using very fine micropipette-electrode made of
polished glass and the current passing through the membrane
can be measured by maintaining a current across the membrane.

Most of the ion channels identified can exist in an open or a
closed confirmation. Such channels are said to be gated. 3
major categories of gated channels are distinguished as:
a) Voltage gated channel: conformational state depends on the
difference in ionic charge on the two sides of the membrane.
b) Ligand gated channels: conformational state depends on the
binding of a specific molecule(ligand) which is usually not the
solute that passes through it. Some gates open on the binding
of ligand on the outer surface of the channel and some open
on binding on the inside.
c) Mechano gated channels: conformational state depends on
mechanical forces that are applied to the membrane.

 Diffusing substance first binds selectively to a membrane
spanning protein called a facilitative transporter.
 Binding of solute to transporter trigger conformational change
in protein, exposing solute to the other surface of the
membrane.
 Can facilitate the movement in both directions.
 Much like enzymatic reactions; transporters are specific for
solutes, discriminating D and L isomers.
 Like enzymes, their activity is regulated.
 Glucose transporter is an example for facilitated diffusion.

 Like facilitated diffusion, active transport depends on integral
membrane protein that selectively bind a particular solute and
move it across the membrane in a process driven by changes
in protein’s conformation.
 Movement of solute against concentration gradient requires
the coupled input of energy.
 Coupled with exergonic process such as hydrolysis ofATP,
absorbance of light, transport of electrons, or flow of other
substances down their concentration gradient.
 Proteins often refered to as ‘pumps’
 In 1957 Jens Skou discovered an ATP hydrolysing enzyme in
nerve cell of crab that was only active in the presence of Na+
and K+. The enzyme was called Na+/K+ ATPase or Sodium
Pottasium pump.

Membrane structure

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