Lecture 2

Question 1

Functions for cell membranes

Answer 1

•Defines the cell

–Creates an intracellular and extracellular space

•Separates compartments

–Separation of outside environment allows specialized chemical reactions to proceed.

–Allows diverse chemical reactions to occur in close proximity

•Controls movement of molecules

–Nutrients (specialized pumps and channels span the membrane)

–Waste (as above)

–Information (receptors)

Question 2

More functions for membranes

Answer 2

•Generation of gradients

–Gradients store energy (like a battery)

–Nerve cells use voltage gradients to power electrical signaling

–Many other cells use concentration gradients to drive pumps

•Serve as a scaffold for assembling large molecular complexes

–Generation of ATP by mitochondria

–Detection of light by photoreceptors

–Many other signal transduction events

•Serve as a resource for materials

–The membrane is “mined” by the cell to generate intracellular signaling molecules.

Question 3

Phospholipid structure

Answer 3

• Phospholipids are major constituents of the membrane
• Phospholipids consist of glycerol, fatty acids (FA), and a polar head group
• Phospholipids are amphipathic.

–The fatty acids are uncharged and do not readily associate with water.

–The head group has a charge and thus “likes” to associate with water.

(Not the exact picture in the slide)

Question 4

Fatty Acids Hide From Water in 2 Ways

Answer 4

Create a micelle

Create a bilayer

• Both structures can form spontaneously depending on the conditions (temperature, ionic strength, etc.)
• The fatty acids form a hydrophobic barrier which keeps charged molecules from crossing from one side of the membrane to the other

Question 5

Properties of

Phospholipid Bilayers

Answer 5

•Spontaneous formation in an aqueous environment.

–Compartments favored (membranes fold and seal to avoid edges)

–Infinitely extensive

•Forces create barriers to movement

–Van der Waals forces: fatty acids

–Electrostatic forces: polar head groups and water

•Membranes are 2 dimensional solutions

–Lipids diffuse rapidly within one layer but cannot spontaneously flip to the other layer.

Interactions between water and the polar head groups

Question 6

Saturated and Unsaturated Fatty Acids

Question 7

Unsaturated Fatty Acids Disturb the Membrane Structure

Question 8

Other components of the membrane- Sphingolipids

Answer 8

•Sphingolipids

–These molecules use sphingosine as the backbone instead of glycerol.

Question 9

Other components of the membrane- Cholesterol

Answer 9

•Cholesterol

–An amphipathic ring structure

Question 10

Sphingolipids

Answer 10

• Sphingolipids represent the second large class of membrane lipids.
• If one adds a fatty acid to sphingosine it becomes ceramide.
• Ceramide is the actual parent compound for all sphingolipids

Question 11

Gangliosides

Answer 11

• Gangliosides contain sugars instead of a head group.
• The simplest form is cerebroside

–It contains either a glucose or galactose

•More complex gangliosides have up to 7 levels of branched sugars.

–Most terminate in acidic sugars known as sialic acids.

Question 12

Gangliosides are often sites of biological recognition

Answer 12

• Gangliosides are not uniformly distributed throughout a membrane.
• Instead they appear to associate with proteins involved in signaling.

–Gangliosides appear to be structurally vital for the assembly of lipid rafts (signaling platforms within the membrane “ocean”).

• The highest concentrations of gangliosides are found in the brain where they constitute 6% of lipids.
• Ganglioside populations can change dramatically during development and also during tumor progression.

–Efforts are underway to try to identify tumor cells by the gangliosides they express.

Question 13

Gangliosides determine blood groups

Answer 13

•The carbohydrate moieties on sphingolipids define the three human blood groups.

Question 14

Ganglioside diseases

Answer 14

•Several human diseases are caused by disruptions of ganglioside breakdown.

–Gangliosides are degraded inside of lysosomes.

–Degradation involves the sequential removal of sugars.

Question 15

Ganglioside diseases

Tay-Sachs

Answer 15

•Tay-Sachs disease: loss of ability to remove the terminal N-acetylgalactosamine residue (GM2 processing defect)

–Children with Tay-Sachs suffer from weakness and retardation and die by age 3.

–Their neurons become swollen with lipid-filled lysosomes and undergo either apoptosis or autophagy

Question 16

Ganglioside diseases

Guillain-Barre syndrome

Answer 16

•Guillain-Barre syndrome: an acute inflammatory disease usually triggered by a strong infection affecting the peripheral nervous system.

–Autoantibodies produced against gangliosides damage axons

Question 17

Ganglioside diseases

Alzheimer’s disease

Answer 17

•Alzheimer’s disease: amyloid b-protein deposits

–Too much ganglioside GM1 contributes to aggregation

Question 18

Cholesterol Modulates Membrane Fluidity-

Cholesterol inserts into the membrane

Answer 18

•Cholesterol inserts into the membrane

–The hydroxyl group of cholesterol is charged while the rings and tail of cholesterol are neutral.

–Thus cholesterol is amphipathic and inserts with its rings pointing into the membrane and its hydroxyl pointing outward.

Question 19

Cholesterol Modulates Membrane Fluidity-

Maintenance of cell membrane integrity

Answer 19

•Maintenance of cell membrane integrity

–The rings of cholesterol interact with its neighboring fatty acids

–Because cholesterol is rigid it adds some firmness to the membrane

–Cholesterol also decreases the general permeability of the membrane to small water soluble molecules.

Question 20

Cholesterol Modulates Membrane Fluidity-

Maintenance of membrane fluidity

Answer 20

•Maintenance of membrane fluidity

–Cholesterol also breaks up interactions between fatty acids

Question 21

Cholesterol Modulates Membrane Fluidity

Answer 21

•We might say that cholesterol keeps the membrane from extreme states: not too fluid … not too stiff… just right.

KNOW!!!!!!

Question 22

Cholesterol is found in

lipid rafts

Answer 22

• Unlike gangliosides, cholesterol does NOT have sugar chains that contain some information.
• Like gangliosides, cholesterol is enriched in lipid rafts.

–Indeed, lipid rafts are made up primarily of sphingolipids and cholesterol in the outer exoplasmic leaflet.

–These are connected to phospholipids and cholesterol within the inner cytoplasmic leaflet.

•Certain transmembrane receptors prefer to float within the raft environment.

–The properties of the raft environment seem to be important in the modulation of the activity of these receptors.

Question 23

Human Diseases for which Raft Proteins are Targets

Answer 23

• Alzheimer’s disease
• Parkinson’s disease
• Osteoporosis
• Atherosclerosis
• Diabetes
• Cancer
• Asthma
• (and many others)

Question 24

Lipid Rafts and

Alzheimer’s Disease

Answer 24

•The amyloid ß-peptide (Aß) is derived from the cleavage of a larger protein.

–Aß is considered to be a major contributor to amyloid plaques that kill neurons

• Different cleavage enzymes partition differently into lipid rafts.
• Cholesterol depletion experiments in animal models show that Aß formation is decreased.

–Suggests that cholesterol levels ARE important (at least for Aß formation)

•The ε4 allele of the apoE gene (a carrier that delivers cholesterol within the CNS) is a major risk factor for Alzheimer’s Disease.

–Genetic evidence links cholesterol levels to Alzheimer’s Disease

Question 25

Proteins Add Function to Membranes-Myelin

Answer 25

•Myelin membrane functions to insulate the electrical signals passed by axons.

–An example of a function requiring no protein.

–Protein content of myelin is less than 25% of the membrane.

Question 26

Proteins Add Function to Membranes

Answer 26

• Many (but not all) of the functions of the membrane involve proteins that actually perform that function.
• A typical plasma membrane is somewhere between these two extremes.

–Approximately 50% protein.

Question 27

Proteins Add Function to Membranes- Mitochondrial

Answer 27

•Mitochondrial membranes are involved in the production of ATP.

–An example of a function that requires a LOT of proteins.

–Protein content of the internal mitochondrial membrane is approximately 75%.

Question 28

Proteins Associate with the Membrane in

Different Ways

Answer 28

1. A single transmembrane alpha helix.
2. Multiple alpha helices span the membrane.
3. A rolled up beta sheet (beta barrel) spans the membrane.
4. An alpha helix only spans one leaflet of the membrane.
5. A lipid is covalently attached to the protein and inserts into the inner leaflet.
6. A membrane associated protein interacts via non-covalent binding to an oligosaccharide.
7. An intracellular membrane associated protein interacts with an integral membrane protein.
8. An extracellular membrane associated protein interacts with an integral membrane protein.

Question 29

The Membrane Spanning Alpha Helix

Answer 29

• Amino acids of the protein are in a completely lipid environment.
• Most of these amino acids must be uncharged for insertion to be energetically favorable.
• Peptide bonds are polar, however, so they must form hydrogen bonds.
• The alpha helix maximizes the number of hydrogen bonds that can be made between these amino acids while maintaining an uncharged outer surface that interacts with the hydrophobic tails.

Question 30

The Membrane Spanning Alpha Helix

Question 31

Membranes can be Separated into Domains- Tight Junction

Answer 31

•A specialized cellular structure called a tight junction can limit the diffusion of material.

–Tight junctions are created by membrane proteins to create a diffusion barrier.

–For example, epithelial cells in the picture below have an apical membrane (away from the basal lamina) and a basolateral membrane (associated with the basal lamina).

–Protein A and protein B are unable to diffuse past the tight junction

•The cell places different proteins in these different membranes.

-The endoplasmic reticulum sorts membrane proteins, sending them to their destination.

Question 32

Membranes can be Separated into Domains- Tight Junction

(image)

Question 33

**Cells in Tissues Have Apical and Basal Sides **

Question 34

Restricting the Mobility of Proteins

Question 35

Biological membranes are complex

Question 36

Summary

Answer 36

• Cell membranes serve many purposes.
• Membranes consist of phospholipids, cholesterol, sphingolipids, and proteins and have special properties.
• Membranes are not homogeneous mixtures; cholesterol, sphingolipids, and certain signaling proteins are concentrated in lipid rafts.
• Membranes are connected to the cytoskeleton within the cell and the ECM without the cell.
• A number of diseases have been associated with membrane components (such as gangliosides) and with lipid rafts.