Notesale: Turn your study into money

Document Preview

Extracts from the notes are below, to see the PDF you'll receive please use the links above

---

LIPID DYNAMICS IN MEMBRANES
Diffusion occurs within membranes

•

Lateral diffusion of lipids
o Very fast; D=1μm2
...
e
...


•
•

Mobility increases towards the bilayer centre
Tm depends upon
o Length of chain
o Degree of unsaturation
• Certain membrane transport processes and enzyme activities cease when the bilayer
viscosity is increased beyond a threshold level
• A synthetic bilayer made from a single type of phospholipid:
o Changes from a liquid state to a two-dimensional rigid crystalline (or gel)
state at a characteristic freezing point – phase transition – lower if
hydrocarbons are short or have double bonds
▪ Longer hydrocarbon chains – more interactions along length
▪ Less double bonds – less kinks – hydrocarbon chains are closer – more
interactions
Acyl chain melting temperatures
No
...
g
...
Bacteria, yeasts and
other organisms whose temperature fluctuates with that of their environment adjust the
fatty acid composition of their membrane lipids to maintain a relatively constant fluidity
...

Lipids and disease
There are many known lipid-associated diseases
• Lipid storage diseases
• Metabolic diseases
• Transport diseases
Example: Adrenoleukodystrophy (ALD) and Lorenzo’s oil
• ALD
o X-linked metabolic disorder
▪ Only boys
▪ Onset 6-10
o Build up of very long chain saturated fatty acids
o Destroys myelin sheath
o Neurological disability and death
• Preventative treatment
o Lorenzo’s oil
▪ 4:1 mixture of glycerol trioleate and glycerol trierucate
▪ Competitively inhibits VLFCA forming enzymes

Sterols
• Phospholipids
o Charged
o Neutral
• Sphingolipids
• Glycolipids
• Steroids
o Animal – cholesterol
o Yeast – ergosterol
o Plants – stigmasterol
Membrane fluidity: influence of cholesterol
In eukaryotes cholesterol also regulates membrane fluidity
...
At high concentrations (found in most eukaryotes), it prevents
the crystallisation of hydrocarbon chains, which thereby inhibits the phase transition,
making it more fluid
...


Cholesterol also influences membrane fluidity
More ordered acyl chains are longer, so the membrane is thicker
...
It inserts
into the bilayer with its hydroxyl group close to the polar head groups of the phospholipids
so that its rigid, plate-like steroid rings interact with and partially immobilise those regions
of the hydrocarbon chain closest to the polar head groups
...
Although cholesterol tightens
the packing of the lipids in a bilayer, it does not make membranes any less fluid
...

Percentage of total lipid by weight
Red blood
Mitochondrion
Liver cell
Lipid
cell
(inner and
Endoplasmic
E
...
In
archaea, lipids usually contain 20-25 carbon-long prenyl chains instead of fatty acids, prenyl
and fatty acid chains are similarly hydrophobic and flexible
...
The plasma
membranes of most eukaryotic cells are more varied than those of prokaryotes and
archaea, not only in containing large amounts of cholesterol but also in containing a mixture
of different phospholipids
...
Some of this is due to the
variation in head groups, hydrocarbon chain lengths and desaturation of the major
phospholipid classes, but there are also many structurally distinct minor lipids
...

Membranes have asymmetric lipid distributions

Lipid asymmetry:
• Asymmetric synthesis, specific lipid transport/translocation
• Minimal spontaneous flip-flop
Plasma membrane lipid asymmetry – why is it important?
• In the extracellular space
o Cell-cell interaction
▪ Glycolipids are important for the interaction with other cells and the
extracellular matrix
• In the cytosol
o Cell signalling
▪ PS in outer PM leaflet – apoptotic signal triggers phagocytosis by
macrophages
o Recruitment of proteins to the membrane

▪

Many proteins bind to PL head groups e
...
phosphoinositide-binding
proteins in cytosol
How are phospholipids synthesised?
• Each step is catalysed by enzymes in the ER membrane that have their active site
facing the cytosol, where all of the required metabolites are found
• When the fatty acids arrive in the ER membrane, they are activated with CoA
• Glycerol-3-phosphate acyl transferases add a fatty acid to phosphoglycerol to make
lysophosphatidate
• Glycerol-3-phosphate acyl transferase add a fatty acid to lysophosphatidate to make
phosphatidate (phosphatidic acid) which is sufficiently insoluble to stay in the lipid
bilayer, and it cannot be extracted from the bilayer by the fatty acid binding
proteins
...
falciparum amplified a gene encoding an ABC
transporter that pumps out chloroquine
• Cystic fibrosis (mutated CFTR – cystic fibrosis transmembrane conductance regulator
protein)
o Discovered through studies of cystic fibrosis
o Mutation in CFTR – functions as a Cl- channel in the plasma membrane of
epithelial cells
o CFTR regulates ion concentrations in the extracellular fluid, especially in the
lungs
o 1/27 Caucasians carries a gene encoding a mutant form of this protein
o 1/2900, both copies of the gene are mutated – this causes the disease
o In contrast to other ABC transporters, ATP binding and hydrolysis do not
drive the transport process – instead, control the opening and closing of Cl-,
which provides a passive conduit for Cl- to move down its electrochemical
gradient
• Tangier disease (mutated ABCA1)
o Orange tonsils, enlarged liver and spleen
o Mediates efflux of cholesterol from cytosolic to outer leaflet of PM
o Disease leads to accumulation of cholesterol in cells
• Sitosterolaemia (mutated ABCG5 and ABCG8)
o Increased intestinal sterol absorption
o Decreased secretion of sterol into bile
o ABC mediate sterol uptake and efflux
Mitochondria, peroxisomes and plastids
• Not connected to ER via vesicular transport system
• No de novo lipid synthesis, therefore lipids are transported from the ER
• Monomeric diffusion of lipids is energetically unfavourable
...

• Animal cells synthesise phosphatidylserine and phosphatidylcholine in the
endoplasmic reticulum and then transfer them to the outer membrane of
mitochondria
...
Mitochondria and plastids are not part of this system and therefore require
different mechanisms to import lipids and proteins for growth

•

o They import most of their proteins from the cytosol
o They do not synthesise lipids de novo – their lipids are imported from the ER
So how do lipids get from the ER to other organelles? By lipid transfer proteins

Phospholipid exchange proteins
Lipids are insoluble in wat

---