10.2 Structural Lipids in Membranes

Common principles of membrane lipids

Membrane lipids are amphipathic molecules with a polar head and a non-polar hydrocarbon portion
In water the hydrophobic parts cluster, ordering of surrounding water falls and free energy decreases, the hydrophobic effect
Lipids with two long chains generally form bilayers well
Single-chain surfactants readily form micelles, though head size and conditions change the assembly
The membrane interior is hydrophobic, so ions and most polar molecules cross only slowly
Gases and some small non-polar molecules permeate relatively easily
Lipids diffuse laterally and rotate within a leaflet, while flip-flop between leaflets has a high energy barrier
Flippases, floppases and scramblases regulate transverse movement
Longer chains pack more tightly and many cis double bonds lower the transition temperature
Real fluidity depends on temperature, cholesterol, lipid type, proteins and ions together

Figure 10.2-1Composition of amphipathic lipids and the principle of bilayer formation

Glycerophospholipids are derivatives of phosphatidic acid

The backbone is glycerol with fatty acids esterified at sn-1 and sn-2 and phosphate at sn-3
The simplest form, phosphatidic acid, is diacylglycerol plus phosphate
Adding an alcoholic head group gives PC, PE, PS or PI
PC and PE carry ammonium and phosphate charges that nearly cancel, giving net charge near zero but not the absence of charge
The charge of PS and PI depends on pH and ionic environment
The prefix phosphatidyl denotes the shared glycerol, two acyl chains and phosphate
With the same shared part, a different head group changes surface electrostatics and protein binding
Not every membrane has the same lipid proportions

Figure 10.2-2Representative motions of membrane lipids and their timescales

Ester and ether linkages

In ordinary glycerophospholipids the fatty acid carboxyl forms an ester with glycerol, giving the -O-C(=O)- arrangement
In some membrane phospholipids the sn-1 position is an ether link
Plasmalogens carry a vinyl ether at sn-1, and platelet-activating factor is another ether lipid
The two linkages differ in susceptibility to hydrolysis
Ether links are not automatically stable under all conditions, and vinyl ethers can be oxidation-sensitive
Archaeal lipids are distinguished by isoprenoid chains attached through ether bonds
Most animal and plant glycerophospholipids use ester bonds, with ether lipids as the exception
Absence of a carbonyl band in an infrared spectrum is a clue, though other carbonyl groups must be considered

Figure 10.2-3Connectivity of phosphatidic acid; R denotes different hydrocarbon chains

Figure 10.2-4Key chemical difference between ester and ether linkages

Chloroplast galactolipids and sulfolipids

The chloroplast thylakoid membrane differs markedly in lipid composition from animal membranes
Main components are MGDG with one galactose, DGDG with two, SQDG with a sulfoquinovose head and the anionic phospholipid PG
MGDG and DGDG are galactolipids without phosphate
MGDG favours negative curvature while DGDG favours bilayer formation
SQDG is an anionic sulfolipid and PG is an anionic phospholipid
Under phosphate limitation some plants shift toward non-phosphorus lipids
PG function cannot be fully replaced in every case
The claim that phospholipids are the main component of every biological membrane has a clear counterexample in thylakoids

Figure 10.2-5Representative lipid types of the thylakoid membrane; proportions are illustrative

The distinctive design of archaeal membrane lipids

Archaeal lipids use a glycerol-1-phosphate backbone with branched isoprenoid chains attached by ether bonds
This differs in stereochemistry from the sn-glycerol-3-phosphate lipids of bacteria and eukaryotes
The difference is a clue to evolutionary relationships
Diether lipids can form a bilayer where the two leaflets meet
Tetraether lipids span the membrane to create a monolayer-type membrane
This contributes to stability and low permeability in thermophilic and acidophilic archaea
Not every archaeon has only a tetraether monolayer
Thermal stability of a membrane cannot be judged from structure alone, since proteins and internal environment also act

Figure 10.2-6Archaeal diether bilayer compared with a tetraether monolayer-spanning membrane

Sphingolipids are derivatives of sphingosine

The backbone is the long-chain amino alcohol sphingosine rather than glycerol
A fatty acid joined to the amino group by an amide bond gives ceramide
Adding different polar heads to ceramide yields the various sphingolipids
Sphingomyelin is ceramide with phosphocholine, rarely phosphoethanolamine
Its head resembles phosphatidylcholine but the backbone is sphingosine, not glycerol
Glycosphingolipids carry sugars and include cerebroside, globoside and ganglioside classes
Sphingomyelin counts as a phospholipid but not as a glycerophospholipid
The two questions use different criteria, head group and backbone

Figure 10.2-7Structural relation from sphingosine to ceramide and the sphingolipid classes

Glycosphingolipid glycans are addresses for cell recognition

The oligosaccharide heads of many glycosphingolipids face the outside of the membrane
Glycan arrangement and sugar identity carry information for cell interaction, differentiation and pathogen or toxin binding
Some gangliosides are binding targets for particular toxins and proteins
Surface recognition also involves glycoproteins, receptors and protein complexes, not glycolipids alone
ABO antigens reflect terminal glycan differences and occur on both glycolipids and glycoproteins
The claim that ABO antigens consist only of glycosphingolipids is wrong
The glycocalyx is built from several classes of glycoconjugate together
GM1 is one target for the B subunit of cholera toxin, and recognition depends on glycan shape and exposure more than on a single sugar

Figure 10.2-8Glycans of glycosphingolipids protruding from the membrane and cell recognition

Breakdown and recycling of phospholipids and sphingolipids

Phospholipases are a family of enzymes that cleave different bonds in phospholipids
PLA1 cleaves the sn-1 acyl chain and PLA2 the sn-2 chain, releasing a free fatty acid and a lysophospholipid
PLC hydrolyses between glycerol and phosphate while PLD hydrolyses between phosphate and head group
Cleavage of an sn-2 arachidonyl chain by PLA2 releases arachidonate as a signalling precursor
Not every PLA2 substrate carries arachidonate at sn-2
Membrane components reach lysosomes through uptake, autophagy and membrane turnover
In the acidic lysosome, hydrolases and accessory proteins break down lipids stepwise
Complex glycosphingolipids lose sugar residues sequentially from the glycan end
Loss of an enzyme or accessory protein causes a specific substrate to accumulate, determined by the blocked step
The useful chain of reasoning is gene, then enzyme or transport function, then stored substrate, then cell damage

Figure 10.2-9Typical cleavage sites of phospholipases

Figure 10.2-10Lysosomal breakdown and recycling of membrane lipids and the consequence of a blocked step

Sterols: four fused rings

A sterol has a common skeleton of three six-membered rings fused to one five-membered ring
Cholesterol is the main animal membrane sterol, with a small polar hydroxyl, a rigid ring system and a hydrocarbon tail
The hydroxyl sits near phospholipid heads while the rest lies inside the membrane
Cholesterol limits excessive fluidity at high temperature and hinders tight packing at low temperature
It therefore buffers fluidity changes, though the claim that it always increases fluidity is wrong
Animals use cholesterol, fungi ergosterol and plants phytosterols such as sitosterol and campesterol
Most bacterial membranes lack sterols, with exceptions
Mechanical behaviour depends on sterols together with chain composition and proteins

Figure 10.2-11A to D rings of a sterol with the polar hydroxyl and non-polar portion of cholesterol

Figure 10.2-12Cholesterol positioned among phospholipids in an animal membrane

Why one membrane needs many lipids

A membrane is not a homogeneous sheet of one substance but a structure built from head charges, saturation, curvature, sterols and proteins together
The two leaflets generally differ in composition, and this asymmetry matters for signalling and function
Phosphatidylserine is more abundant on the cytosolic leaflet of normal animal cells
During apoptosis PS becomes exposed on the outer surface
Under some conditions cholesterol- and sphingolipid-rich local regions form transiently as lipid rafts
Rafts are a useful concept, though assuming fixed, stable islands of constant size in every membrane is an oversimplification
The integrated logic runs from backbone to head charge and linkage, then to prediction of assembly, fluidity, recognition and breakdown, then to data
Example: 1,600 phospholipids out of 2,000 total lipids is 80 mol percent, and 240 PS is 12 mol percent
With PC and PE at zero and PS and PI at -1, the mean formal charge per lipid is (240 plus 200) over 2,000, or -0.22 e

Figure 10.2-13Simulated data comparing lipid composition of the two leaflets