Download Lecture: 10-14-16

Lecture: 10‐14‐16
CHAPTER 12
Membrane Structure and Function
Cell membranes are not static structures and they show irregularities called ruffles and spikes
Fibroblast cell Chapter 12 Outline
Characteristics of membranes:
1. Membranes are sheet‐like structures, two molecules thick that form closed boundaries between different compartments. Thickness of most membranes are between 6‐10 nm
2. Membranes are composed of lipids and proteins, either of which can be decorated with carbohydrates.
3. Membrane lipids are small amphipathic molecules that form closed bimolecular sheets that prevent the movement of polar or charged molecules.
4. Proteins (pumps, channels, receptors, energy transcducers, and enzymes), serve to mitigate or diminish the impermeability of membranes and allow movement of molecules and information across the cell membrane.
5. Membranes are noncovalent assemblies. Protein and lipid molecules held together by many noncovalent interactions.
6. Membranes are asymmetric in that the outer surface is always different from the inner surface.
7. Membranes are fluid structures. Lipid and protein molecules diffuse rapidly in the plane of the membrane.
Electron micrograph A section of a phospholipid bilayer membrane
Phospholipids and glycolipids form lipid bilayers in aqueous solutions.
What are the energetic forces contributing to the formation of membrane?
The formation of membranes is powered by mainly the hydrophobic effect. In addition, van der Waals attractive forces between hydrocarbon tails and electrostatic and hydrogen‐bonding between the polar head groups and water molecules
A space‐filling model A liposome or Lipid Vesicle
Clinical insight or utility
Liposomes formed by sonicating a mixture of phospholipids in aqueous solution, are useful tool for studying membrane permeability and for targeted drug‐delivery (e.g. therapeutic DNA or small molecule) systems.
The preparation of glycine‐
containing liposomes
Most personal care industry uses this system to deliver vitamins and other chemicals to rejuvenate the skin The ability of small molecules to cross a membrane is a function of its hydrophobicity.
Indole is more soluble than tryptophan in membranes because it is uncharged. Ions
cannot cross membranes because of the energy cost of shedding their associated water molecules.
Dissolvation‐‐resolvation
Permeability coefficients of ions and molecules in a lipid bilayer.
The permeability coefficient (P), expressed in cm s1, provides a quantitative estimate of the rate of a molecule to travers a membrane.
Permeability of small molecules is correlated with their solubility in water and nonpolar solvents
Membrane processes or dynamic activities depend on the fluidity of the membrane.
The temperature at which a membrane transitions from being highly ordered to very fluid or disordered is called the melting temperature.
The melting temperature is dependent on the length of the fatty acids in the membrane lipid and the degree of cis unsaturation.
Cholesterol helps to maintain proper membrane fluidity in membranes in animals.
The phase‐transition, or melting, temperature (Tm) for a phospholipid membrane
The packing of fatty acid chains in a membrane.
The highly ordered packing of fatty acid chains is disrupted by the presence of cis double bonds.
Three molecules of stearate (C18, saturated) Oleate (C18, unsaturated) between two molecules of stearate
Cholesterol disrupts the tight packing of the fatty acid chains in mammalian.
Cholosterol is inserted into the bilayer with its long axis perpendicular to the plane of the membrane. Choleterol’s hydroxyl group forms a hydrogen bound with a carbonyl oxygen atom of a phospholipid head group, whereas its hydrocarbon is located in the nonpolar core of the bilayer. Cholesterol also interacts with saturated fatty acid compartment forming a membrane domain called lipid rafts Membrane lipids establish a permeability barrier; however,
membrane proteins allow transport of molecules and information across the membrane.
Membranes vary in protein content from as little as 18% to as much as 75%.
In general, membranes performing different functions contain different kinds and amount of proteins.
a, b) Integral membrane proteins are embedded in the hydrocarbon core of the membrane.
c, d) Peripheral membrane proteins are bound to the polar head groups of membrane lipids or to the exposed surfaces of integral membrane proteins by electrostatic
and hydrogen bond interactions.
Integral and peripheral membrane proteins
e) Some proteins are associated with membranes by attachment to a hydrophobic moiety that is inserted into the membrane. Lipid bilayer has dual functions:
a) acts a solvent for integral membrane proteins and (b) form a permeability barrier
Structure of bacteriorhodopsin, an integral membrane protein
Membrane‐spanning α helices are a common structural feature of integral membrane proteins.
Other means of embedding integral membrane proteins is by using β strands to form a pore in the membrane or by embedding part of the protein into the membrane. Structure of bacteriorhodopsin
The structure of bacterial porin
The cyclooxygenase (COX) activity of prostaglandin H2 synthase‐1 is dependent on a channel connecting the active site to the membrane interior.
Aspirin inhibits cyclooxygenase activity by obstructing the channel.
The hydrophobic channel of prostaglandin H2
synthase‐1.
The attachment of prostaglandin H2 synthase‐1 to the membrane
Mechanism: Aspirin acts by transferring an acetyl group to a serine residue in prostaglandin H2 synthase‐1.
Fluorescence recovery after photobleaching (FRAP) is a technique that allows the measurement of lateral mobility of membrane components.
A membrane component is attached to a fluorescent molecule. On a very small portion of the membrane, the dye is subsequently destroyed by high‐intensity light, thereby bleaching a portion of the membrane.
The mobility of the fluorescently labeled component is a function of how rapidly the bleached area recovers fluorescence.
Lateral diffusion of proteins depends on whether they are attached to other cellular or extracellular components.
The technique of fluorescence recovery after photobleaching
(FRAP).
Lipid movement in membranes.
Lipids rapidly diffuse laterally in membranes, although the rotation of lipids from one face of the membrane to the other, a process called a transverse diffusion or flip‐flopping, is very rare without the assistance of enzymes.
Protein do not rotate across bilayes. The prohibition of transverse diffusion
of proteins preserves for the stability of membrane asymmetry.
A small molecule will spontaneously cross a membrane if two conditions are met:
1. The concentration of the molecule is higher on one side of the membrane than the other.
2. The molecule is lipophilic or soluble in nonpolar solutions.
Molecules meeting these criteria can simply diffuse across the cell membrane.
Polar molecules can diffuse across a membrane down their concentration gradient
only with the assistance of a particular protein called a channel. Such movement is called facilitated diffusion or passive transport.
Transport proteins function as pumps or channels to facilitate the flow of small molecules across the cell membrane.
Movement of molecules against a concentration gradient requires a source of energy and is called active transport.
Types or Classes of Transport Proteins The Na+‐K+ ATPase or Na+‐K+ pump uses the energy of ATP hydrolysis to simultaneously pump three Na+ ions out of the cell and two K+ ions into the cell against their concentration gradients.
Because the reaction includes an intermediate in which the enzyme is phosphorylated, such pumps are called P‐type ATPases. Na+‐K+ pump: ATP‐driven pump Another prominent class of membrane pumps is the ABC transporters, so named because they all contain a domain that binds ATP, called the ATP‐binding cassette.
Members of this class include the multidrug resistance protein (MDR), which pumps drugs out of a cell, and the cystic fibrosis transmembrane conductance regulator, which acts as a chloride channel. Mutations in this protein lead to cystic fibrosis.
Harlequin ichthyosis is a severe pathological condition that results from a mutation in an ABC transporter in a common form of skin cells.
Symporters power the transport of a molecule against its concentration gradient by coupling the movement to the movement of another molecule down its concentration gradient, with both molecules moving in the same direction.
Example: Glucose is moved into some animal cells against its concentration gradient by a symporter that is powered by Na+ ions moving down a concentration gradient.
Antiporters also use one concentration gradient to power the formation of another, but the molecules move in opposite directions. Na+ (out) vs. K+ (in)
antiporter
Secondary transport
Symporter
Cardiotonic steroids, such as digitalis, strengthen heart contractions and are used to treat heart disease. It is a choice drug to treat congestive hear failure.
One means of removing Ca2+ from the cell is by a Na+/Ca2+ antiporter. By inhibiting the Na+‐K+ ATPase, Ca2+ ions remain in the cell longer, leading to a more robust heart contraction. Digitalis is isolated from the dried leaf of the foxglove plant, Digitalis purpurea.
foxglove plant
Ion channels are passive transport systems that allow specific and rapid transport of ions down their concentration gradients.
Channels can be activated by changes in the voltage across a membrane (voltage‐
activated channels) or by binding of specific molecules to the channels (ligand‐
activated channels).
Tetrodotoxin, produced by the puffer fish, is a lethal inhibitor of the Na+ channel. Puffer fish
Transient receptor potential (TRP) channels play a variety of roles in animals such as rattlesnake. Venomous pit vipers use TRP channels to generate a thermal image that is overlaid on their visual image to assist in hunting.
[Left: Michiel de Wit/ Shutterstock; right: Ted Kinsman/Science Source.]
The potassium channel, one of the most studied channel, selectively and rapidly transports K+ across the cell membrane. Larger ions are not transported because they are too big to enter the channel.
Smaller ions are excluded because they cannot interact with the selectivity filter. Such ions are small enough that the energy of desolvation cannot be compensated for by interactions with the selectivity filter.
The energetic basis of ion selectivity.
The energy cost of dehydrating a potassium ion is compensated by favorable interactions with the selectivity filter. Because a sodium ion is too small to interact favorably with the selectivity filter, the free energy of desolvation cannot be compensated, and the sodium ion does not pass through the channel. Charge repulsion among the four ion binding sites in the potassium channel accounts for the rapid transport of K+ ions down their concentration gradient.
The selectivity filter has four binding sites (white circles). Hydrated potassium ions can enter these sites, one at a time, losing their hydration shells (red lines). When two ions occupy adjacent sites, electrostatic repulsion forces them apart. Thus, as ions enter the channel from one side, other ions are pushed out the other side. A model for K+‐channel transport.