Membrane Structure

Plasma Membrane
THE LIPID BILAYER
MEMBRANE PROTEINS

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Cell membranes act as selective barriers
 The plasma membrane is involved in cell communication,
import and export of molecules, and cell growth and motility
Membranes form the different compartments in a Euk cell
The cell membrane (plasma
membrane or plasmalemma)
encloses or covers all cell types
and is 7 nanometers (7 x 109 M)
thick
 THE LIPID BILAYER
• Membrane Lipids Form Bilayers in Water
• The Lipid Bilayer Is a Two-dimensional Fluid
• The Fluidity of a Lipid Bilayer Depends on Its
Composition
• The Lipid Bilayer Is Asymmetrical
• Lipid Asymmetry Is Preserved During
Membrane Transport
 Membrane Lipids Form Bilayers in Water

Lipid components of the bilayer

Phospholipids
• Phosphoglycerides: glycerol, 2 fatty acids and polar head
group
• Sphingolipids: sphingosine, 1 fatty acid and polar head group
Other lipids:
• Steroids (cholesterol mainly)
• Fatty acids: aliphatic chains with carboxylic acid group

Protein components of the bilayer

Simple proteins
Glycoproteins:
Proteins with carbohydrate chains
Proteoglycans:
Proteins with glycosaminoglycan chains
 HYDROPHILIC

HYDROPHOBIC

Essential Cell Biology (© Garland Science 2010)

AMPHIPATHIC
 Self-Sealing

Essential Cell Biology (© Garland Science 2010)

Essential Cell Biology (© Garland Science 2010)
The Lipid Bilayer Is
a Two-dimensional
Fluid
 Fluidity of Lipid Bilayer
• Rapid lateral diffusion of phospholipids 10-8cm/sec
• Change places 107 times/sec
• Rarely flip-flop
• Fluidity depends on composition (phospholipid and cholesterol)
and temperature
• Phase transition= the temperature at which there is a change of
state from liquid to solid

Essential Cell Biology (© Garland Science 2010)

 The Fluidity of a Lipid Bilayer Depends on
Its Composition
Fluidity and length and saturation
of FA hydrocarbon chains
• Short hydrocarbon chain lengths ↑ TEMPARATURE
fluidity
• Double bonds ↑ fluidity

 Fluidity and cholesterol content

Cholesterol ↑ fluidity
 Provides mechanical stability
 1 cholesterol/phospholipid in eucaryotes
 No cholesterol in procaryotes;
mechanical stabililty imparted by cell wall

20% OF TOTAL
LIPID BY WEIGHT
Domain formation Vs Fluidity
Essential Cell Biology (© Garland Science 2010) The Lipid Raft
Lipid Raft (Sphingo and Cholesterol)
Lateral Segregation
Protein stabilized

Molecular Biology of the Cell (© Garland Science 2008)

Lipid Droplets
• The Lipid Bilayer Is Asymmetrical
• Phospholipid distribution: phosphatidylcholine and
sphingomyelin confined to outer monolayer
phosphatidylethanolamine, phosphatidylserine and
phosphatidalinositol are on inner monolayer
• Cholesterol
• Charge & Proteins
• Impt to function (ie, apoptosis and translocation of
phosphatidylserine)
• glycolipids

Essential Cell Biology (© Garland Science 2010)

 Membrane asymmetry
• The lipid asymmetry is
established and maintained as
the membrane grows
• Enzyme catalyzed deposition of
all newly made PLs in the
cytosolic half of the Bilayer
• Slective flippase
• Nearly all membrane
synthesized at ER

Essential Cell Biology (© Garland Science 2010)

 PL SER & PLIn
PKC Binds to the PL-Ser to
exert its effect

PLIn and Signalling

PL-SER
assymetry to
distinguished
between Live &
Dead Cells
 Glycolipids
• Made from Sphingosine,
• Only outside. (5% of all lipid in outer monolayer)
• Enzymatic Glycosilation takes place in GA resmbles ECS.
• Most abundant in PM of neurons

• Can serve as
receptor
 Preservation of Lipid Assymetry
• The cytosolic face is always
adjacent to the cytosol, while
the noncytosolic face is
exposed to either the cell
exterior or the interior space
of an organelle
• Glycolipids in Gogi aparatus

• Inositol inner membrane

Essential Cell Biology (© Garland Science 2010)

 MEMBRANE PROTEINS
• Membrane Proteins Associate with the Lipid
Bilayer in Various Ways
• A Polypeptide Chain Usually Crosses the
Bilayer as an  Helix
• Membrane Proteins Can Be Solubilized in
Detergents and Purified
• The Complete Structure Is Known for
Relatively Few Membrane Proteins
• The Plasma Membrane Is Reinforced by the
Cell Cortex
• Cells Can Restrict the Movement of Membrane
Proteins
• The Cell Surface Is Coated with Carbohydrate
 MEMBRANE PROTEINS
 Proteins Carry Out Specific Functions of Membrane
o Give each type of membrane characteristic functional properties
o Amounts and types of proteins highly variable
o By mass proteins represent 50% lipids; lipids small thus 1
protein/50 lipid molecules
o Associate w/ membrane in various ways depending on function:
transmembrane, integral, peripheral
 Membrane proteins associate with the
lipid bilayer in Various Ways

Essential Cell Biology (© Garland Science 2010)

Transmembrane Proteins Typically Cross as Alpha Helix

• Unique orientation

• Insertion in ER

• Membrane spanning doamin

comprised of nonpolar aa 20-30

• Alpha helix is predominate

conformation but beta sheets form

closed beta barrels that can span
membrane as well
• Can predict membrane spanning

regions via hydropathy plot

Multipass α-helix
 Multipass α-helix formation

Figure 10-25 Molecular Biology of the Cell (© Garland Science 2008)

Beta Barrels form Transmembrane Channels
• Tend to be more rigid

• Comprised of 8-22 strands

• Some pore forming proteins

generating water-filled
channels for select hydrophilic
solutes
• Polar side chains line channel
on inside; nonpolar side chains
project out interact
w/hydrophobic core of lipid
bilayer
Membrane Proteins can be Solubolized and Purified in Detergents
 Distrupt hydrophobic interactions
Bind to hydrophobic regions of
membrane and displace lipid molecules
SDS, triton
 The Plasma Membrane Is
Reinforced by the Cell Cortex
The Cortical Cytoskeleton: Red Blood Cells
 Model system for studying membranes
 Available in large numbers
 Easy to isolate uncontaminated from other
cell types
 Can prepare ghosts and in-side-out vesicles
 Red Blood Cells
Ghosts and InSide-Out RBCs
Ghosts= empty RBCs prepared by placing cells in soln of low
salt to cause water to move into and lyse cells
can reseal or be studied while leaky
Inside-Out Vesicles
 Studies of RBC Plasma Membrane Proteins by SDS PAGE

 15 major protein bands btwn 15,000-

250,000 daltons
 3 most prominent comprose more than
65% protein mass; ea arranged
differently in membrane
– Spectrin
– Glycophorin
– Band 3
 Spectrin= Cytoskeletal Protein Assoc. w/
Cytosolic Side of Membrane
 Most proteins are peripheral and assoc w/ cytosolic side
 Spectrin most abundant
 Long, thin, flexible rod 100 nm length, constitutes 25% protein mass
 2.5 x 105 copies/cell
 Principle component of cytoskeleton underlying RBC, maintains structural integrity
and biconcave shape
 Heterodimer formed from 2 lg structurally similar subunits that assoc head to head
to form 200 nm long tetramer
 Tail ends of 4-5 tetramers linked by binidng short actin filaments and other
cytoskeletal components forming meshwork
 Abnormalities in spectrin results in anemia and spherical shaped RBCs that are
fragile
 Ankyrin binds spectrin and band 3 to membrane
Glycophorin
 Some singlepass glycoprotein of 131 aa
 Most of mass on external surface of membrane
 100 sugar residues on 16 different side chains which
account for 60% protein mass
 >90% sialic acid most of negative charge on surface of
RBC
 1 million molecule/cell
 Function unknown

Band 3
 Multipass membrane protein
 Catalyzes couple transport of anions
 930 aa thought to extend across
bilayer 12X
 Allows HCO3 to cross membrane in
exchange for Cl- increasing amount
of CO2 delivered to lungs
Cells Can Restrict the Movement of Membrane Proteins
• Proteins can move freely within
the plane of the lipid bilayer
• NOT ALL PROTEINS
• In specific membrane domains
cells are proteins are confined
and restricted to move to other
regions
• Cells can create barriers that
restrict particular membrane
components to one membrane
domain
 The Cell Surface Is Coated with Carbohydrate
• Non-Cytosolic Side: Glycoproteins, Proteoglycan, Glycolipids
• Protect the cell surface from mechanical and chemical damage
• Carbohydrate layer can absorb water→ Slimy surface
• Cell-cell recognition and adhesion
• Cell identity
• Chemotaxis
 Membrane Transport
• PRINCIPLES OF MEMBRANE TRANSPORT
• TRANSPORTERS AND THEIR FUNCTIONS
• ION CHANNELS AND THE MEMBRANE
POTENTIAL
• ION CHANNELS AND SIGNALING IN NERVE
CELLS
PRINCIPLES OF MEMBRANE TRANSPORT
• The Ion Concentrations Inside a Cell Are Very
Different from Those Outside
– Internal ion composition is very different than external
– Crucial for cells survival and function
– Cell and its surrounding are elctrically neutral
PRINCIPLES OF MEMBRANE TRANSPORT
• Lipid Bilayers are
Impermeable to Solutes
and Ions
– Given enough time, virtually
any molecule will diffuse
across a lipid bilayer
– Diffusion rate depends on
• Size and Solubility in lipid
• Solubility increases as size
decrease.
PRINCIPLES OF MEMBRANE TRANSPORT

• Membrane Transport Proteins Fall into Two

Classes: Transporters and Channels
– Each type of membrane therefore has its own
characteristic set of transport proteins
– Channels: size and electric charge
– Transporters: solute specific binding site, transport
involves conformational changes
PRINCIPLES OF MEMBRANE TRANSPORT

• Solutes Cross Membranes by Passive or

Active Transport
– Concentration gradient is the key
TRANSPORTERS AND THEIR FUNCTIONS
• Required for the movement of almost all small
organic molecules across cell membranes
• Highly selective
• Specific location
– Each cell type or organelle has (some) specific
transporters
 TRANSPORTERS AND THEIR
FUNCTIONS
• Concentration Gradients and Electrical Forces
Drive Passive Transport
• Active Transport Moves Solutes Against Their
Electrochemical Gradients
• Animal Cells Use the Energy of ATP Hydrolysis to
Pump Out Na+
• The Na+-K+ Pump Is Driven by the Transient
Addition of a Phosphate Group
• The Na+-K+ Pump Helps Maintain the Osmotic
Balance of Animal Cells
• Intracellular Ca2+ Concentrations Are Kept Low by
Ca2+ Pumps
• Coupled Transporters Exploit Gradients to Take
Up Nutrients Actively
• H+ Gradients Are Used to Drive Membrane
Transport in Plants, Fungi, and Bacteria
TRANSPORTERS AND THEIR FUNCTIONS
• Concentration Gradients and Electrical Forces
Drive Passive Transport
TRANSPORTERS AND THEIR FUNCTIONS
• Active Transport Moves Solutes Against Their
Electrochemical Gradients
– The ATP-driven Na+/H+ pump has crucialrole in
membrane transport in animal cells
 TRANSPORTERS AND THEIR FUNCTIONS
• Animal Cells Use the Energy of ATP Hydrolysis to
Pump Out Na+
– Na+-K+ ATPase
– 30% or more total ATP consumption

Essential Cell Biology (© Garland Science 2010)

TRANSPORTERS AND THEIR FUNCTIONS

Essential Cell Biology (© Garland Science 2010)

TRANSPORTERS AND THEIR FUNCTIONS
• The Na+-K+ Pump Is Driven by the Transient
Addition of a Phosphate Group
• The Na+-K+ Pump Helps Maintain the Osmotic Balance of
Animal Cells
TRANSPORTERS AND THEIR FUNCTIONS
• Intracellular Ca2+ Concentrations are Kept Low by
Ca2+ Pumps
• Cytosolic 10-4 mM external or organelle 1-2 mM
• Ca++ act as 2nd messenger

Essential Cell Biology (© Garland Science 2010)

TRANSPORTERS AND THEIR FUNCTIONS
• Coupled Transporters Exploit Gradients to Take
Up Nutrients Actively
• Mobilization of Glucose in the GUT
– Lumen to intestinal cells: Na+-Glucose Symport (A)
– Intestinal cells to Plasma: Glucose transporter (P)

Essential Cell Biology (© Garland Science 2010)

TRANSPORTERS AND THEIR FUNCTIONS
• H+ Gradients are used to Drive Membrane
Transport in Plants, Fungi, and Bacteria
 ION CHANNELS AND THE
MEMBRANE POTENTIAL
• Ion Channels Are Ion-selective and Gated
• Ion Channels Randomly Snap Between Open
and Closed States
• Voltage-gated Ion Channels Respond to the
Membrane Potential
• Membrane Potential Is Governed by
Membrane Permeability to Specific Ions
ION CHANNELS AND THE MEMBRANE POTENTIAL
• Hydrophilic channel for small water-soluble
molecule
• Transmembrane narrow, highly selective
aqueous pore
• Gap Junctions between cells and porins in the
outer membrane of mitochondria and in some
Bacteria (Large)
• Channels for Na+, K+, Cl–, and Ca2+
ION CHANNELS AND THE MEMBRANE POTENTIAL
• Ion Channels Are Ion-selective and Gated
• Depends on the diameter and shape of the ion channel and on
the distribution of the charged amino acids
• Ion channels Briefly Open and Close
• No need for conformational change once it is open (faster)
• Ion channels – Change in membrane potential
ION CHANNELS AND THE MEMBRANE POTENTIAL
• Ion Channels
Randomly
Snap Between
Open and
Closed States
• Patch Clamp
Recording: Detection
and measurement of
the electric current
flowing through a
single channel
molecule
 ION CHANNELS AND THE MEMBRANE POTENTIAL

Figure 12-24 Essential Cell Biology (© Garland Science 2010)

ION CHANNELS AND THE MEMBRANE POTENTIAL
• Different Types of Stimuli Influence the
Opening and Closing of Ion Channels
• Selectivity and Gating
ION CHANNELS AND THE MEMBRANE POTENTIAL

Essential Cell Biology (© Garland Science 2010)

ION CHANNELS AND THE MEMBRANE POTENTIAL
• Voltage-gated Ion Channels Respond to the
Membrane Potential
• Voltage Sensors
• A change in the membrane potential does not affect how
wide the channel is open but alters the probability that it
will be found in its open conformation
• Ion channels → membrane potential → ion channels
ION CHANNELS AND THE MEMBRANE POTENTIAL
• Membrane Potential Is Governed by
Membrane Permeability to Specific Ions
• Electrons and Ions/ Na+-K+ pump / K+ leak
channels
• K+ equilibrium and 0 (zero) electrochemical
Gradient
• Net Charge outside or inside is neutral.
• Membrane potential is measured across the
membrane.
ION CHANNELS AND THE MEMBRANE POTENTIAL
 ION CHANNELS AND SIGNALING
IN NERVE CELLS
• Action Potentials Provide for Rapid Long-Distance
Communication
• Action Potentials Are Usually Mediated by Voltage-
gated Na+ Channels
• Voltage-gated Ca2+ Channels Convert Electrical
Signals into Chemical Signals at Nerve Terminals
• Transmitter-gated Channels in Target Cells
Convert Chemical Signals Back into Electrical
Signals
• Neurons Receive Both Excitatory and Inhibitory
Inputs
• Transmitter-gated Ion Channels Are Major Targets
for Psychoactive Drugs
• Synaptic Connections Enable You to Think, Act,
and Remember
 Membrane Potential
• All cells have membrane potential
• Excitable tissues And Non Excitable tissues
• Resting membrane potential
• The unequal distribution of a few key ions between the ICF and
ECF and their selective movement through the plasma
membrane are responsible for the electrical properties of the
membrane
• Na+–K+ pump
• Na+ and K+ alone
Water is the most abundant molecule in an organism

• H2O MW = 18
• Density ~ 1 kg/l

• Therefore the concentration of water in an aqueous solution

is ~ (1000 g/liter )/(18 g/mol) = 55 mol/liter or 55 M.

• All other molecules in the body are at least 100 times less
concentrated.

• Therefore we need to understand the properties of water.

One clue to a cell’s ionic concentrations: Sea Water

Sea Water Extracellular Intracellular

conc (Cytosol)
Na+ 457 mM 145 mM 15 mM
major
monovalent K+ 9.7 mM 4 mM 150 mM
Ions 536 mM 110 mM 10 mM
Cl-

divalent 2+ 10 mM 2 mM 10-8 M
Ca
cations
Mg2+ 56 mM 2 mM 0.5 mM

Pi-2 0.7 mM 2 mM 40 mM
Other ions
H+ 10-7 M 10-7 M 10-7 M

Protein 0.2 mM 4 mM
 Membranes provide a barrier to diffusion around cells,
forming compartments

nicotine

Alberts 4th 11-1

© Garland natural or synthetic
lipid bilayer

. . . But specialized proteins

(channels and transporters)
control the permeation of
many molecules
69
 A Cell that Lacks Concentration Gradients

Na+
Na +
Na+
External
Monovalent cations:
High Na+
Low K+ Na+ +
Na Na+
Na+ K+
Internal:
same as Na+
External Na+ Na+
Na+

Na+ K+
Na +
 Storing energy in a concentration gradient
without osmotic stress:
Simply reverse the ratio of Na+ and K+
Na+
Na +
Na+
External
Monovalent cations:
High Na+
Low K+ K+
K+ K+
Na+
Internal:
Low Na+ K+
High K+ K+ Na+
Na+

Na+ K+
Na +
 The “Na+ pump” splits ATP to make a Na+ and K+
concentration gradient

A transporter (or pump) protein moves a few ions for each conformational change
Converting a concentration gradient to an electrical potential:
Create permeability to one ionic species (K+)

Na+
Na +
Na+

K+
Lost positive charge
leads to net negative
interior potential
Na+ K+
K +

K+
K+ Na+
Na+

K+ channels
Hundreds or thousands of ions flow through a channel protein for each
opening
Na+
Na+
 The Nernst potential
The energy of discharging the concentration gradient for
K+ ions balances the energy of moving the K+ ions back
through the potential difference

K+

K+
K +

K+
K+
Deriving the Nernst potential (chemistry units)
K RT  K i 
G  RT ln i  zFV ; at equilibrium G  0 ; therefore V  ln  
Ko zF  K o 
(we’ll assume that z = +1)

An e-fold ratio of K+ concentration ( K i  K o )

RT
therefore leads to a potential difference of  .
F
R = 1.99 cal/mol oK; T = 300o; F = 9.65 x 104 C/mol (C is abbrev for coulomb).

cal
RT 1.99 mol    300
Therefore = 4 C
 6  10 3
cal/C.
F 9.965 10
mol

Now, 1 cal = 4.18 J (J is the abbreviation for joule),

and 1 J = 1 V x 1 C.

RT
Therefore = 6 10 3 cal/C  4.18 V  C cal  25 mV .
F

Thus an e-fold concentration ratio gives a -25 mV membrane potential.

 What is the selective advantage . . .
that the membrane is permeable at rest to K+ rather than to Na+?

A small inward leak of Na+ would change the internal [Na+]

by fractionally MORE than
A small outward leakage of K+ would change internal [K+ ]

Na+
Na+
[K+]I = 140 mM; [Na+]I = 10 mM. A leak of 10 mM:
[Na+] would increase from ~ 10 mM to 20 mM,
Na+ doubling [Na+]I and causing a 17 mV change in the
Nernst potential.
But a similar outward leak in K+ would decrease [K+]i
from 140 mM to 130 mM, causing a < 2 mV change in
the Nernst potential for [K+]. Na+
Na+ Conclusion: cell function is more stable when the
resting permeability is to K+ .

Na+
Na+ Na+ 76
 What is the selective advantage . . .
that the membrane is permeable at rest to K+ rather than to Na+?

Conclusion: cell function is more stable when the

resting permeability is to K+ .

Na+
Na+

Indeed, there are many dozens of K+

Na+ channels in the genome, but only ~ 10 Na+
channels.
K channels are metabolically “free” at rest.
Important, because the “Na/K pump” splits ~
2/3 of the brain’s ATP. Na+
Na+

Na+
Na+ Na+ 77
Membrane Potential
Equilibrium potential for K+ Equilibrium potential for Na+
Membrane Potential (Electrical Disequilibrium)