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Membrane Structure 357

The distribution of the lipids between the inner and aqueous compartment and consisting of the head group
outer leaflet of a biological membrane is asymmetric, proper, the glycerol backbone, and the ester linkages. The
with the outer surface being enriched in phosphatidyl- molecular details of the membrane surface, including the
choline (PC) and the inner, cytosolic surface in phos- electric surface charges, are relevant for membrane recog-
phatidylethanolamine (PE) and phosphatidylserine (PS). nition by molecules such as enzymes dissolved in the
As a result, the outer lipid membrane surface is electri- extra- and intracellular space. The hydrophobic core re-
cally neutral and the inner negatively charged. Sponta- gion of membranes is formed by the fatty acyl chains of
neous randomization (flip-flop) of zwitterionic lipids be- lipids. The order and dynamics of the hydrophobic core
tween the two leaflets is extremely slow. Specific transport determine the permeability of the membrane to molecules
proteins, belonging to the adenosine triphosphate (ATP) such as drugs and may modulate the function of trans-
binding cassette, further maintain lipid asymmetry. Lipid membrane proteins. In addition to these elelments, we
asymmetry may play a role for the proper orientation of will also discuss the interaction of the lipid membrane
membrane proteins. with amphiphilic molecules, which penetrate into the hy-
The lipid composition of natural membranes is quite drophobic core region, and with intrinsic membrane pro-
heterogeneous. The large variability with respect to head teins. The NMR results obtained by solid-state NMR will
groups, chain length, and extent of cis-unsaturation re- be compared with those obtained with neutron and X-ray
sults in thousands of chemically different lipids. For ex- diffraction and with recent molecular dynamics simula-
ample, the membrane of the red blood cell contains about tions of membranes.
400 chemically different lipids. The lipid composition and
the lipid-to-protein ratio of a given membrane are rela-
tively well defined, suggesting a correlation between lipid II. MEMBRANE LIPIDS
composition and membrane function. At present, little is
known of how the lipid composition is controlled and why Naturallyoccurringlipidscanbedividedessentiallyintwo
biological membranes contain so many different lipids. groups: (1) phospholipids containing glycerophosphate as
Many biological membranes can adapt to changing exter- the anchor group for fatty acids, and (2) lipids contain-
nal conditions such as temperature or long-term exposure ing backbones other than glycerol. Phospholipids may be
to drugs or alcohol by modifying their lipid composition further subdivided into nitrogen-containing lipids, such
in order to maintain the optimal conditions for cell growth. as phosphatidylcholine (PC), -ethanolamine (PE), -serine
Hydrophobic membrane proteins and lipids are diffi- (PS), and plasmalogens, and nitrogen-lacking lipids, such
cult to crystallize compared to water-soluble biological as phosphatidic acid (PA), phosphatidylglycerols (PG),
molecules. Consequently, structural information on mem- cardiolipin (CL), and phosphoinositols (PI). Examples for
brane components has become available at a much slower lipids not containing the glycerol backbone are the sphin-
pace than on water-soluble proteins or DNA. golipids and glycosphingolipids, derived from sphingo-
The situation is even worse for membrane lipids. Not a sine or dihydrosphingosine and are mainly found in nerve
single, naturally occurring phospholipid with unsaturated cells and in brain. Sphingolipids comprise ceramides and
hydrocarbon chains has yet been crystallized. However, sphingomyelins, whereas glycosphingolipids can be sub-
nearly 40 crystal structures of closely related synthetic divided into cerebrosides and gangliosides, both bear-
glycerolipidswithsaturatedhydrocarbonchainshavebeen ing carbohydrate head groups as characteristic structural
solved by X-ray. On the structural level, little is known elements.Animportantlipidcomponentineukaryotic(but
about the interactions of proteins with lipid bilayer en- not in prokaryotic) cells are the sterols with cholesterol as
vironments. Detergent molecules have been detected in the principal representative.
some of the X-ray structures, and a small number of stud- The lipids in eukaryotic cell membranes are mainly
ies discuss lipids bound to proteins. An example is cy- nitrogen-containing phospholipids. They are involved in
tochrome C oxidase crystals, where the lipids were found the maintenance of the barrier properties of membranes
to be arranged in a bilayer structure. and provide the optimal conditions for transmembrane
Magnetic resonance techniques, in particular phos- protein functioning. Some phospholipids also play a deci-
2
31
phorus ( P) and deuterium ( H) magnetic resonance, sive role in cell signaling processes. Phosphatidic acid was
in combination with selectively deuterated lipids, have shown to enhance the membrane binding of phospholipase
yielded quantitative information on the ordering, motional C-β 1 and to stimulate hydrolysis of phosphatidylinositol
anisotropy, and dynamics of membrane components. This 4,5-bisphosphate (PIP 2 ), resulting in the formation of di-
information is essential for understanding the function of acylglycerol and inositol 1,4,5-triphosphate. The released
biological membranes. diacylglycerols may then further activate kinases.
The different structural elements of the lipid membrane Sphingolipidsandglycosphingolipidsarebelievedtobe
include the polar part, constituting the interface to the structural as well as signaling constituents of membranes.