CELL MEMBRANE

The lipid bilayer

The lipid bilayer has been firmly established as the universal basis of

membrane structure, and its properties are responsible for the general

properties of all cell membranes. Because cells are filled with—and surrounded

by—solutions of molecules in water, we begin this section by

considering how the structure of cell membranes is a consequence of the

way membrane lipids behave in a watery (aqueous) environment.

Membrane lipids Form bilayers in Water

The lipids in cell membranes combine two very different properties in a

single molecule: each lipid has a hydrophilic (“water-loving”) head and

one or two hydrophobic (“water-fearing”) hydrocarbon tails.

The most abundant lipids in cell membranes are the phospholipids,

molecules in which the hydrophilic head is linked to the rest of the lipid

through a phosphate group. The most common type of phospholipid

in most cell membranes is phosphatidylcholine, which has the small

molecule choline attached to a phosphate as its hydrophilic head and two

long hydrocarbon chains as its hydrophobic tails.

Molecules with both hydrophilic and hydrophobic properties are termed

amphipathic. This chemical property is also shared by other types of

membrane lipids, including the sterols (such as the cholesterol found in

animal cell membranes) and the glycolipids, which have sugars as part

of their hydrophilic head. Having both hydrophilic and

hydrophobic parts plays a crucial part in driving these lipid molecules to

assemble into bilayers in an aqueous environment.

Hydrophilic molecules dissolve readily in water

because they contain charged atoms or polar groups, that is, chemical

groups with an uneven distribution of positive and negative charges; these

charged atoms can form electrostatic attractions or hydrogen bonds with

water molecules, which are themselves polar. Hydrophobic

molecules, by contrast, are insoluble in water because all—or almost

all—of their atoms are uncharged and nonpolar; they, therefore, cannot

form favorable interactions with water molecules. Instead, these nonpolar

atoms force adjacent water molecules to reorganize into a cagelike

structure around the hydrophobic molecule. Because the

cagelike structure is more highly ordered than the surrounding water,

its formation requires energy. The energy cost is minimized, however, if

the hydrophobic molecules cluster together, limiting their contact with

water to the smallest possible number of water molecules. Thus, purely

hydrophobic molecules, like the fats found in animal fat cells and the oils

found in plant seeds, coalesce into a single large drop

when dispersed in water.

the molecules of the bilayer will spontaneously rearrange to eliminate

the free edge. If the tear is small, this spontaneous rearrangement will

exclude the water molecules and lead to repair of the bilayer, restoring

a single continuous sheet. If the tear is large, the sheet may begin to fold

in on itself and break up into separate closed vesicles. In either case, the

overriding principle is that free edges are quickly eliminated.

The prohibition on free edges has a profound consequence: the only way

a finite sheet can avoid having free edges is to bend and seal, forming a

boundary around a closed space. Therefore, amphipathic

molecules such as phospholipids necessarily assemble into self-sealing

containers that define closed compartments. This remarkable behavior,

fundamental to the creation of a living cell, is in essence simply a result

of the property that each molecule is hydrophilic at one end and hydrophobic

at the other.

the lipid bilayer is a two-dimensional Fluid

The aqueous environment inside and outside a cell prevents membrane

lipids from escaping from the bilayer, but nothing stops these molecules

from moving about and changing places with one another within the

plane of the bilayer. The membrane therefore behaves as a twodimensional

fluid, which is crucial for membrane function and integrity . this property is distinct from flexibility, which is the ability of

the membrane to bend. Membrane flexibility is also important, and it sets

a lower limit of about 25 nm to the size of vesicle that cell membranes

can form.

The fluidity of lipid bilayers can be studied using synthetic lipid bilayers,

which are easily produced by the spontaneous aggregation of amphipathic

lipid molecules in water. Two types of synthetic lipid bilayers are

commonly used in experiments. Closed spherical vesicles, called liposomes,

form if pure phospholipids are added to water; they vary in size

from about 25 nm to 1 mm in diameter. Alternatively, flat

phospholipid bilayers can be formed across a hole in a partition between

two aqueous compartments.

These simple artificial bilayers allow measurements of the movements

of the lipid molecules, revealing that some types of movement are rare

while others are frequent and rapid. Thus, in synthetic lipid bilayers,

phospholipid molecules very rarely tumble from one half of the bilayer,

or monolayer, to the other. Without proteins to facilitate the process

and under conditions similar to those in a cell, it is estimated that this

event, called ‘flip-flop,’ occurs less than once a month for any individual

lipid molecule. On the other hand, as the result of thermal motions, lipid

molecules within a monolayer continuously exchange places with their neighbors.

This exchange leads to rapid diffusion of lipid molecules in the plane of the membrane so that, for example, a lipid in an artificial bilayer may diffuse a length equal to that of a large bacterial cell (~2 mm) in about one second. If the temperature is decreased, the drop in thermal energy decreases the rate of lipid movement, making the bilayer less fluid.

Similar results are obtained when one examines isolated cell membranes

and whole cells, indicating that the lipid bilayer of a cell membrane

also behaves as a two-dimensional fluid in which the constituent lipid

molecules are free to move within their own layer in any direction in the

plane of the membrane. These studies also show that lipid hydrocarbon

chains are flexible and that individual lipid molecules within a monolayer

rotate very rapidly about their long axis—some reaching speeds of 30,000

revolutions per minute . In cells, as in synthetic bilayers,

individual phospholipid molecules are normally confined to their own

monolayer and do not flip-flop spontaneously.

the Fluidity of a lipid bilayer depends on its Composition

The fluidity of a cell membrane—the ease with which its lipid molecules

move within the plane of the bilayer—is important for membrane function

and has to be maintained within certain limits. Just how fluid a lipid

bilayer is at a given temperature depends on its phospholipid composition

and, in particular, on the nature of the hydrocarbon tails: the closer

and more regular the packing of the tails, the more viscous and less fluid

the bilayer will be. Two major properties of hydrocarbon tails affect how

tightly they pack in the bilayer: their length and the number of double

bonds they contain.

A shorter chain length reduces the tendency of the hydrocarbon tails

to interact with one another and therefore increases the fluidity of the

bilayer. The hydrocarbon tails of membrane phospholipids vary in length

between 14 and 24 carbon atoms, with 18–20 atoms being most usual.

Most phospholipids contain one hydrocarbon tail that has one or more

double bonds between adjacent carbon atoms, and a second tail with

single bonds only. The chain that harbors a double bond

does not contain the maximum number of hydrogen atoms that could, in

principle, be attached to its carbon backbone; it is thus said to be unsaturated with respect to hydrogen. The fatty acid tail with no double bonds has a full complement of hydrogen atoms; it is said to be saturated. Each double bond in an unsaturated tail creates a small kink in the hydro-carbon tail, which makes it more difficult for the tails

to pack against one another. For this reason, lipid bilayers that contain

a large proportion of unsaturated hydrocarbon tails are more fluid than

those with lower proportions.

In bacterial and yeast cells, which have to adapt to varying temperatures,

both the lengths and the unsaturation of the hydrocarbon tails in the

bilayer are constantly adjusted to maintain the membrane at a relatively

constant fluidity: at higher temperatures, for example, the cell makes

membrane lipids with tails that are longer and that contain fewer double

bonds. A similar trick is used in the manufacture of margarine from

vegetable oils. The fats produced by plants are generally unsaturated and

therefore liquid at room temperatures, unlike animal fats such as butter

or lard, which are generally saturated and therefore solid at room temperature.

Margarine is made of hydrogenated vegetable oils; their double

bonds have been removed by the addition of hydrogen so that they are

more solid and butterlike at room temperature.

In animal cells, membrane fluidity is modulated by the inclusion of the

sterol cholesterol. This molecule is present in especially

large amounts in the plasma membrane, where it constitutes approximately

20% of the lipids in the membrane by weight. Because cholesterol

molecules are short and rigid, they fill the spaces between neighboring

phospholipid molecules left by the kinks in their unsaturated hydrocarbon

tails. In this way, cholesterol tends to stiffen the

bilayer, making it more rigid and less permeable. The chemical properties

of membrane lipids—and how they affect membrane fluidity.

For all cells, membrane fluidity is important for many reasons. It enables

membrane proteins to diffuse rapidly in the plane of the bilayer and to

interact with one another, as is crucial, for example, in cell signaling. It permits membrane lipids and proteins to diffuse

from sites where they are inserted into the bilayer after their synthesis to

other regions of the cell. It allows membranes to fuse with one another

and mix their molecules, and it ensures that membrane molecules are

distributed evenly between daughter cells when a cell divides. If biological

membranes were not fluid, it is hard to imagine how cells could live,

grow, and reproduce.

Cell membranes are generally asymmetrical: they present a very different

face to the interior of the cell or organelle than they show to the exterior.

The two halves of the bilayer often include strikingly different sets ofphospholipids and glycolipids. Moreover, membrane proteins

are embedded in the bilayer with a specific orientation, which is

crucial for their function.

the lipid bilayer is asymmetrical

lipid asymmetry is preserved during Membrane transport

The lipid asymmetry is established and maintained as the membrane

grows. In eucaryotic cells, new phospholipids are manufactured by

enzymes bound to the part of the endoplasmic reticulum membrane that

faces the cytosol. These enzymes, which use free fatty acids as substrates

, deposit all newly made phospholipids into the cytosolic half of the bilayer. To enable the membrane as a whole to grow evenly, half of the new phospholipid molecules then have to be transferred to the opposite monolayer. This transfer is catalyzed by enzymes called flippases . In the plasma membrane, flippases transfer specific phospholipids selectively, so that different types become concentrated in each monolayer.

Using selective flippases is not the only way to produce asymmetry in

lipid bilayers, however. In particular, a different mechanism operates for

glycolipids—the lipids that show the most striking and consistent asymmetric

distribution in animal cells. To explain their

distribution, it is necessary to take a more detailed look at how new

membrane is produced in eucaryotic cells.

Nearly all new membrane synthesis in eucaryotic cells occurs in the

membrane of one intracellular compartment—the endoplasmic reticulum .

The new membrane assembled there is exported to the other membranes

of the cell through a cycle of membrane budding and fusion: bits of the

bilayer pinch off from the ER to form small spheres called vesicles,

which then become incorporated into another membrane,

such as the plasma membrane, by fusing with it. The orientation

of the bilayer relative to the cytosol is preserved during vesicle

formation and fusion. This preservation of orientation means that all cell

membranes, whether the external plasma membrane or an intracellular

membrane around an organelle, have distinct ‘inside’ and ‘outside’ faces

that are established at the time of membrane synthesis: the cytosolic face

is always adjacent to the cytosol, while the noncytosolic face is exposed

to either the cell exterior or the interior space of an organelle.

Glycolipids are located mainly in the plasma membrane, and they are

found only in the noncytosolic half of the bilayer. Their sugar groups are

therefore exposed to the exterior of the cell, where they

form part of a continuous protective coat of carbohydrate that surrounds

most animal cells. The glycolipid molecules acquire their sugar groups

in the Golgi apparatus, the organelle to which proteins and membranes

made in the ER often go next . The enzymes that

add the sugar groups are confined to the inside of the Golgi apparatus, so

that the sugars are added only to lipid molecules in the noncytosolic

half of the lipid bilayer. Once a glycolipid molecule has been created in this

way, it remains trapped in this monolayer, as there are no flippases that

transfer glycolipids to the cytosolic monolayer. Thus, when a glycolipid

molecule is finally delivered to the plasma membrane, it faces away from

the cytosol and displays its sugar on the exterior of the cell.

Other lipid molecules show different types of asymmetric distributions,

related to other functions. The inositol phospholipids, for example, are

minor components of the plasma membrane, but they play a special role

in relaying signals from the cell surface to the intracellular components

that respond to those signals. They act only after the signal has been

transmitted across the plasma membrane; thus they are concentrated

in the cytosolic half of this lipid bilayer.

and others to be exported. Other proteins in the membrane act as sensors that enable the cell to receive information about changes in its environ- ment and respond to them (Figure 11–2). The mechanical properties of the

membrane are equally remarkable. When a cell grows or changes shape,

The simplest bacteria have only a single membrane—the plasma mem- brane. Eucaryotic cells, however, also contain an abundance of internal membranes that enclose intracellular compartments to form the various organelles, including the endoplasmic reticulum, Golgi apparatus, and mitochondria (Figure 11–3). These internal membranes are constructed on the same principles as the plasma membrane, and they, too, serve as highly selective barriers between spaces containing distinct collections of molecules (see Figure 11–1B). Subtle differences in the composition of these membranes, especially in their resident proteins, give each organelle its distinctive character.

Regardless of their location, all cell membranes are composed of lipids and proteins and share a common general structure (Figure 11–4). The lipids are arranged in two closely apposed sheets, forming a lipid bilayer (see Figure 11–4B and C). This lipid bilayer gives the membrane its basic structure and serves as a permeability barrier to most water-soluble mol- ecules. The proteins carry out most of the other functions of the membrane and give different membranes their individual characteristics.

In this chapter we consider the structure of biological membranes and the organization of their two main constituents: lipids and proteins. Although we focus mainly on the plasma membrane, most of the concepts we dis- cuss also apply to internal membranes. The functions of cell membranes, including their role in cell communication, the transport of small mol- ecules, and energy generation, are considered in later chapters.

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cell membrane