The Molecules of the Cell Membrane

Author(s): Mark S. Bretscher

Source: Scientific American , Vol. 253, No. 4 (October 1985), pp. 100-109
Published by: Scientific American, a division of Nature America, Inc.
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 The Molecules of the Cell Metnbrane
They spontaneously form a simple, two-dimensional liquid controlling
what enters and leaves the cell. Some cells internalize and then recycle
a membrane area equivalent to their entire surface in less than an hour

by Mark S. Bretscher

T
he organization of chemical ac­ time other vesicles from the interior cytic cycle. How, given such mixing of
tivity in all higher cells depends of the cell fuse with the plasma mem­ membrane, IS the integrity of each set
in large part on the compartmen­ brane and expel their contents into of membrane proteins maintained?
tation afforded by biological mem­ the surrounding medium. Such pitting

T
branes. The basic building blocks of and fusing circulates membrane from he basic framework of all mem­
membranes are a class of molecules the surface of the cell to its interior branes is a double layer of lipid
called lipids, which by virtue of their and back again. An area of membrane molecules, an arrangement originally
interactions with one another in a wa­ equivalent to the area of the entire sur­ proposed by E. Gorter and F. Grendel
tery medium form a closed and flex­ face of the cell takes part in the cycle of the University of Leiden in 1925.
ible compartment. Embedded in the every 50 minutes. Nature has evolved a variety of lipid
lipid matrix are many different kinds The study of the plasma membrane molecules all of which share a critical
of protein molecules, which give each has focused in recent years on the property: one end of the molecule is
kind of membrane its distinctive iden­ mechanisms that underlie this circu­ soluble in water and is chemically de­
tity and carry out its specialized func­ lation and on its various effects. Al­ scribed as hydrophilic; the other end is
tions. The primary function of all though it has been accepted for some a hydrocarbon, is therefore oily and
membranes, then, is to separate what time that the primary function of the insoluble in water and is chemically
is inside the membrane compartment endocytic cycle is to bring specific nu­ described as hydrophobic.
from the environment outside it. With­ trients into the cell, it is now increas­ The commonest membrane lipids
in the cell, for example, membranes ingly clear that it can serve the cell in belong to a class called the phospho­
serve to isolate the chemical reactions other ways too. For example, my own lipids. They have a hydrophilic head
that take place inside each intracellu­ recent work (which I shall not describe group made up of a phosphate linked
lar organelle. The cell itself is encapsu­ here) suggests that the cell can exploit to a residue that can be either choline,
lated by its own cell membrane: the the endocytic cycle to move about on ethanolamine, serine or inositol. The
plasma membrane. The plasma mem­ a substrate. head group is attached to two hydro­
brane is the best-understood mem­ Another major issue is to under­ phobic tails, each of which is a fatty
brane, and most of this discussion will stand how each kind of membrane, in­ acid chain. The most abundant and
be devoted to it. cluding the plasma membrane, gains most widely studied phospholipid is
Evidently if nutrients are to enter the its own unique set of proteins, which the one having a choline residue. It is
cell or if waste material is to leave it, determines both its identity and its called phosphatidylcholine. Like oth­
the materials must somehow cross the functions. The problem of membrane er phospholipids it has a remarkable
barrier created by the lipid matrix of identity is complicated by the continu­ property: when they are introduced
the plasma membrane. The crossing is al exchange of membrane among the into a watery environment, the individ­
usually effected by globular protein various cellular organelles that takes ual molecules spontaneously arrange
molecules that span the plasma mem­ place, for example, during the endo- themselves into a bilayer. In the bilay-
brane and catalyze the transfer of spe­
cific nutrients and waste molecules.
Some of the nutrient molecules re­
quired by eukaryotic cells are too large
BASKETLIKE NETWORK of protein molecules called clathrin coats a closed, spherical
to be transported across the membrane piece of membrane called a vesicle, which was isolated from a human placenta. The coated
in this way, however. Instead certain vesicle is derived from the plasma membrane of the cell through a dynamic process called
protein receptor molecules, anchored receptor-mediated endocytosis, whereby large molecules are brought into the cell. When
by their tail in the plasma membrane, selected molecules outside the cell become attached to protein receptors in the membrane,
bind these nutrients from the sur­ a coat of clathrin begins to assemble itself on the side of the membrane facing the cell inte­
rounding medium. In a process called rior. Each molecule of clathrin is a chain of about 1,600 amino acids, and the coat is a hon­
endocytosis, pits develop in the mem­ eycomb structure formed when the molecules become aligned in a regular pattern. As the
coat grows, the region of membrane to which it is attached bulges into the cell in a way that
brane and engulf many such receptor
resembles the formation of a drop of water on the lip of a faucet. The bulge pinches off
molecules and their bound nutrients,
from the surface of the cell and becomes a vesicle whose inside surface carries the recep­
which at this stage are called ligands. tors and their ligands and whose outside surface retains the honeycombed coat of clathrin
The pits close up and bud off into the seen in the image. The image was constructed by computer from a series of electron micro­
cell, forming vesicles in the cytoplasm, graphs made at various tilt angles by Guy Vigers of the Medical Research Council's Labo­
or internal fluid of the cell. At the same ratory of Molecular Biology in Cambridge. Enlargement is more than two million diameters.

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er the molecules in both layers align side the vesicle and the fluid outside. ids, and to ions. All are highly soluble
themselves in such a way that their Such vesicles form because if a free in water and insoluble in hydrocarbon
longest axis is roughly perpendicular edge on a bilayer were exposed, some solvents. It is this feature that enables
to the plane of the bilayer. The hydro­ of the hydrophobic regions of the the bilayer to function as a barrier.
philic head groups face water on both phospholipid molecules would be in Second, a bilayer formed from natu­
sides of the bilayer, and the oily, hy­ contact with water; that would be ener­ rally existing phospholipids is a liquid.
drophobic tails sequester themselves getically unfavorable. It is this proper­ There is a double sense in which the
in the middle of the bilayer, thereby ty of lipids that makes them so effec­ bilayer exhibits the random motions
excluding water from it. The arrange­ tive in biological systems: they sponta­ characteristic of the liquid phase. The
ment is\ the state of lowest free energy neously form a closed envelope with hydrocarbon tails of the phospholipid
for these molecules in water. considerable mechanical strength. molecules wiggle about, and so the bi­
In 1965 Alec D. Bangham and his Two general features of the bilay­ layer is soft and flexible-with the vis­
colleagues at the Agricultural Re­ er are important in the formation of cosity of, say, olive oil rather than par­
search Council's Institute of Animal a biological membrane. First, because affin wax. Furthermore, the molecules
Physiology in Cambridge showed that they have a hydrocarbon interior, they can diffuse sideways freely within their
phospholipid bilayers in water form are essentially impermeable to most own monolayer, and so two neighbor­
closed spherical vesicles having two biological molecules, such as amino ing phospholipids in the same mon­
separated compartments: the fluid in- acids, sugars, proteins and nucleic ac- olayer can change places .with each

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other about once every microsecond. tributed on both sides of the bilayer, membranes of animal cells: glycolip­
The phospholipid molecules in oppo­ but in 1972 I discovered that the distri­ ids and cholesterol. The glycolipid
site monolayers, however, almost nev­ bution is much more orderly. In the molecule has a hydrophobic tail simi­
er change places: such an exchange is plasma membrane of the red blood lar to that of sphingomyelin. As its pre­
made, on the average, only about once cell I found the outer monolayer in­ fix implies (glyco- is from the Greek
a year. Hence each monolayer is a cludes only phosphatidylcholine and word for sweet), the glycolipid's hy­
two-dimensional liquid. Physiological­ its close relative, sphingomyelin, both drophilic end is composed of a variety
ly the liquid nature of bilayers is quite of which contain choline. In contrast, of simple sugars joined to form a linear
important. If the bilayer were a rigid the monolayer facing the cytoplasm or branching structure called an oligo­
structure, for example, the nerve cells has phosphatidylethanolamine and saccharide. Glycolipids make up only
in the neck would crack whenever a phosphatidylserine. It is thought that a small fraction of the lipids in the
person nodded. phosphatidylinositol also resides on membrane, and they are confined to
In a natural membrane one might the cytoplasmic side of the bilayer. the outer monolayer.
expect to find the various kinds of In addition to the phospholipids two Cholesterol, on the other hand, is
phospholipid molecules randomly dis- other kinds of lipids are found in the (together with phospholipid) a major
membrane lipid. It is a large, disk­
PHOSPHATIDYLCHOLINE shaped molecule with four carbon
rings that are fused together, giving the
molecule a rigid structure. One end of
·CHOLINE - ETHANOLAMINE cholesterol is hydrophilic, but the rest
of it is hydrophobic and embeds itself
H,C "-... PHOSPHATE H "-....
in the hydrophobic part of the plasma
H - N+ -CH, - CH,- membrane. Roughly equal numbers
H/ of cholesterol and phospholipid mole­
cules are in the plasma membrane of
eukaryotic cells. The addition of cho­
lesterol to the phospholipid matrix
makes the membrane somewhat less
flexible and even less permeable.
Several puzzles about the lipids in
the plasma membrane are still un­
solved. The biological role of the gly­
-INOSITOL

\
colipids, for example, is not yet known.
Nor is there yet any convincing expla­
/ CHOH -- C OH
nation for the distribution of phospho­
lipids in the bilayers. Why are the bi­
CHOH CH--
layers of a eukaryotic cell made up of a

\ CHOH -- L
oH
variety of phospholipids rather than of
only, say, phosphatidylcholine? What
is the function of the phospholipids'
HYDROCARBON asymmetric distribution? Finally, the
CHAINS
geometry of the bilayer itself presents
a problem. The two monolayers are
essentially independent of each other,
but of course they cover the same area.
-SERINE What are the lateral forces in each
monolayer, then? Is one monolayer
H "" under compression and the other un­
der tension, or is the lateral pressure
H-N+ - CH - CH,-
I
the same in both?
H /
coo-

W
hereas the lipids form the matrix
of a membrane, the proteins car­
ry out all its specific functions. The
membrane proteins can be classified
roughly into two general kinds accord­
ing to their shape within the hydrocar­
bon core of the membrane. The shape
of one kind is a rodlike, tightly coiled
spiral called an alpha helix. In this
structure the amino acids that make up
the polypeptide chain are so arranged
that the protein backbone is a helix and
the amino acid side chains project out­
PHOSPHOLIPID MOLECULE is the primary structural element in all cell membranes.
ward from the helix. The second kind
Four main kinds of phospholipid are found in animal-cell membranes. The one shown at
of membrane protein appears to have
the left in the diagram is phosphatidylcholine, but the other three differ from it and from
one another only in the chemical structure of their head groups, which are diagrammed
a substantial globular structure within
here as colored spheres. The electric charge in each head group makes the group hydrophil­ the membrane's hydrophobic region.
ic. The head group is connected to a glycerol group, and two hydrocarbon chains are at­ One of the clearest examples of a
tached in turn to the glycerol. The hydrocarbon chains are oily and therefore hydrophobic. membrane protein with the alpha-he-

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lical structure is glycophorin, the ma­
jor glycoprotein of the red blood cell.
Although its function remains enig­
matic, its structure is now quite well
known. Most of the molecule resides
on the outside of the cell. This extra­
cellular region is a long sequence of
amino acids to which hydrophilic oli­
gosaccharide chains are attached.
In 197 1 I showed that glycophorin
spans the cell membrane. Two years
later Vincent T. Marchesi, who was
then at the National Institute of Ar­
thritis, Metabolism, and Digestive Dis­
eases, suggested the geometry of its
intramembrane domain. He and his
colleagues determined the amino acid
sequence of the protein and found that
its extracellular region is attached to a
segment of 26 hydrophobic amino ac­
ids. The 26 amino acids are joined in
turn to a short hydrophilic tail. The
hydrophobic sequence is just the right
length to span the bilayer as an alpha
helix, and the short hydrophilic tail
rests in the cytoplasm to anchor the
protein in the bilayer.
Many other kinds of membrane pro­
tein are now known to be fixed to the
cell surface by a single hydrophobic
alpha helix and anchored in the cyto­ MOLECULAR ARCHITECTURE of tbe animal-cell membrane is determined primari­
plasm by a hydrophilic tail. Typically ly by tbe interactions of pbospholipid molecules in water. Pbospbolipids can minimize tbeir
they function as receptors for extracel­ energy in water by forming a bilayer about 40 angstrom units tbick. Tbe bydropbobic tails
lular molecules or as highly specific of tbe molecules sequester tbemselves on tbe inside of tbe bilayer and tbe bydropbilic beads

markings (such as the major transplan­ (blue) face tbe water on botb sides of tbe bilayer. If any edge of tbe bilayer were open
to tbe water, bydropbobic tails along tbe edge would be exposed; bence tbe bilayer closes
tation antigens H2 in mice and HLA
to form a vesicle, effectively segregating fluid inside tbe vesicle from fluid surrounding it.
in humans) that enable the immune
system to distinguish foreign invaders
from cells belonging to the organism.
Other proteins in this class include brane, thereby bringing the binding win and Richard Henderson, who were
the surface immunoglobulin receptors site and its attached substrate from one then at the Medical Research Coun­
on B lymphocytes and the spike pro­ side of the membrane to the other. cil's Laboratory of Molecular Biology
teins of many membrane viruses. Since Neither view turned out to be cor­ in Cambridge. Their model shows that
the functioning of such proteins de­ rect. In 197 1 I showed that what is now the polypeptide chain zigzags seven
pends primarily on their extracellular known to be the anion channel spans times across the bilayer. Each trans­
domain, the intramembrane structure the membrane bilayer and has a fixed membrane segment is an alpha helix
need not be extensive. and unique orientation in it. It is now and the helixes are packed together to
thought there is a small passageway form a globular structure. The photon

P
erhaps not surprisingly, the globu­ for anions through the protein, which is captured by a molecule called retinal
lar structure of the second kind of enables them to cross the bilayer. (a relative of vitamin A), which is at­
membrane protein is associated with One of the best-understood globular tached to the protein by a covalent
functions requiring a substantial struc­ membrane proteins is bacteriorhodop­ bond. The mechanism whereby the en­
ture within the plane of the lipid bilay­ sin, which straddles the membrane of ergy of the photon is directed to the
er. For example, one of the most abun­ the bacterium Halobacteriurn halobi­ transport of protons is still not known.
dant proteins in the membrane of the urn. The halobacterium, or salt-loving In eukaryotic cells it is a general
red blood cell is a globular transport bacterium, lives in the salt beds of San rule that all membrane proteins carry
protein called the anion channel. As Francisco Bay. The bacteriorhodopsin an oligosaccharide chain (or several
its name implies, the protein catalyzes in the bacterial membrane is a proton chains) on their extracellular domains,
the passive exchange of negatively pump: it captures photons from sun­ just as glycophorin does. The function
charged ions such as chloride or bicar­ light and exploits their energy to pump of the oligosaccharide chains is ob­
bonate between the blood plasma and protons across the membrane against scure, as it is in the case of the glycolip­
the cytoplasm of the cell. How does an energy gradient. The proton gra­ ids. In addition all membrane proteins,
such a protein function? One early dient generated by the pumping rep­ both globular and alpha-helical, are
scheme suggested the protein might resents potential energy, which later held in place in the bilayer by the same
bind the ion or molecule to be trans­ serves to drive the synthesis of adeno­ kinds of forces that hold the lipid mol­
ported on one side of the membrane, sine triphosphate (ATP). The break­ ecules there: the amino acid side chains
diffuse across the membrane and re­ down of ATP provides energy for the of the protein in contact with the hy­
lease it on the other side. Another bacterium's biosynthetic pathways. drophobic lipid chains are also hydro­
scheme proposed that the protein mol­ The structure of bacteriorhodopsin phobic, whereas the other parts of such
ecule might rotate within the mem- was determined in 1975 by Nigel Un- proteins are hydrophilic. The hydro-

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philic parts are exposed to water on an epithelial sheet. They include the also separates the cell's plasma mem­
each side of the bilayer. cells that line the gut, the dividing cells brane into two domains: the apical
Because all membrane proteins re­ of the skin and the cells of internal or­ surface and the basolateral surface.
side in a liquid bilayer, they can diffuse gans such as the liver, kidney and pan­ Membrane proteins can wander at
sideways just as the lipid molecules do. creas. Epithelial sheets are only one random within their own domain, but
How fast they diffuse is determined in cell thick; often they are folded exten­ the tight junction keeps them from
part by how liquid the phospholipid sively to form a compact organ. moving from one domain to the other.
matrix is. In 1974 Mu-ming Poo and Epithelial sheets have two surfaces. The separation between the two
Richard A. Cone, then at Harvard In the gut, for example, one surface parts of the membrane maintains the
University, showed that rhodopsin (the apical surface) faces the digestive functional asymmetry needed to trans­
diffuses about 10 micrometers in one tract and the other (the basolateral sur­ port material in only one direction.
minute. It seems likely that most other face) faces the blood. Because the epi­ For example, on the apical surface of
membrane proteins diffuse at about thelial gut cells must transport useful the epithelial sheet in the gut each cell
the same rate. Unless they are con­ materials-and only useful materials­ carries proteins that channel sodium
strained from doing so, membrane from the intestine to the blood, the from the gut into the cell. On the baso­
proteins in most eukaryotic cells can cells making up the epithelial sheet lateral membrane there is a different
therefore diffuse, on the average, from must be held together tightly, with no set of proteins that pump the sodium
one end of the cell to the other in a spaces between them. The cells are out of the cell into the blood. The net
few minutes. therefore joined by a set of so-called result is an extremely selective transfer
tight junctions. of sodium ions across the epithelial

T he constraints on the diffusion of

molecules across the membrane
The tight junction can be pictured as
a circular belt or gasket that lies in the
sheet, and it is accomplished because
the specific proteins needed for each
are probably best exemplified in cells plasma membrane. The belt not only step in the transfer are concentrated
that are joined to one another to form prevents leaks (even leaks of ions) but on the part of the membrane sur-

ALPHA-HELIX PROTEIN \ �

�_ _ _ ":::::
� ==::J
GLYCOLIPID

PHOSPHOLIPID
GLOBULAR
PROTEIN
------ �
H YDROPHOBIC
SEGMENT OF
-...:::-
...::: -
-- ......

ALPHA-HELIX PROTEIN

PLASMA MEMBRANE is a phospholipid bilayer in which cholesterol and various kinds

of protein molecules are embedded. In this schematic diagram of the membrane the phos­
pholipid molecules in the top layer, which faces the external medium, are shown as dark
blue spheres each having two wiggly tails. The chaotic Brownian motion of the molecules
within the monolayers is indicated by the diagram at the left; the fluidity of the hydro­
carbon interior is suggested by the random configurations of the tails. The bottom layer,
which faces the cytoplasm inside the cell, has a different phospholipid composition and is
shown in light blue. Although a random exchange of phospholipid molecules also takes
place across the bilayer, the event is extremely rare. Two main kinds of protein in the mem­
brane traverse the bilayer. One kind makes the crossing as a single chain of amino acids
that is coiled into a so-called alpha helix (orange); the intramembrane portion of the sec­
ond kind of protein is globular in structure(red). For clarity the ratio of phospholipid to pro­
tein is much larger here than it is in a natural membrane. Rigid cholesterol molecules (yel­
low) tend to keep the tails of the phospholipids relatively fixed and orderly in the regions
closest to the hydrophilic heads; the parts of the tails closer to the core of the membrane
move about freely. Side chains of sugar molecules attached to proteins and lipids are green.

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face where they can properly carry out OUTSIDE CELL
their role.
How are tight junctions formed, and
how do epithelial cells sort their mem­
brane proteins into two domains? The
first question is still unanswered, but
the second is beginning to yield to at­
tacks based on a discovery by Enrique
Rodriguez Boulan and David D. Sa­
batini of the New York University
School of Medicine in 1978. They
found that when an epithelial sheet
growing in culture is infected with
influenza virus, the progeny viruses
emerge only from the apical surface
of the sheet. On the other hand, a
virus called vesicular stomatitis virus
(VSV), which causes a mild disease in
cattle, emerges only from the basolat­
eral surface. In order to leave its host
cell a virus must assemble a protective
coat, and so Rodriguez Boulan and Sa­
batini concluded that the cell directs
the coat proteins of the influenza virus
to the apical surface and the coat pro­
teins of VSV to the basolateral surface.
The two viruses therefore constitute an
experimental system in which the de­
velopment of asymmetry in epithelial
cells can readily be studied.
The cells that make up an epithelial
sheet can also be joined to one an­ GLOBULAR MEMBRANE PROTEIN bacteriorhodopsin is made up of seven largely
other by a so-called gap junction. The hydrophobic sequences of amino acids, joined by short hydrophilic ones. On the basis of
gap junction is rather like two studs findings by Nigel Unwin and Richard Henderson, who were at the Laboratory of Molecular
Biology when the work was done, it is now thought that each of the seven hydrophobic se­
pressed together with a hole through
quences is an alpha helix (red) embedded in the hydrocarbon core of the membrane and
their middles [see bottom illustration on
that the hydrophilic sequences link the helixes to one another on each side of the membrane
next page]. The hole allows neighbor­ (blue). A molecule called retinal (greell) is attached to the middle of one helix. Retinal cap­
ing cells to communicate and coordi­ tures solar photons, triggering the protein to pump protons across the membrane of certain
nate their activities. Small molecules salt-loving bacteria. The process sets in motion an unusual kind of photosynthesis. The
whose diameter is less than about 20 blue spheres and their tails represent the phospholipid bilayer of the bacterial membrane.
angstroms can pass freely from the cy­
toplasm of one cell through the pipe
formed by the gap junction and into the eukaryotic cell. Recall, nonethe­ integrity. How can specific membrane
the cytoplasm of an adjoining cell. less, that many intracellular organelles proteins, destined for or belonging to
are defined by a limiting membrane a specific organelle, avoid mixing and

T
he structure of gap junctions has and that such membranes play an es­ homogenizing during a transfer? A
been elucidated by Unwin, now sential role in the transpurt, commu­ general and precise answer to the ques­
at Stanford University, and his col­ nication and orderly processing of tion is not yet available, but there is no
leagues. Their work shows that each chemical substances and information doubt that what is transferred is not
junction is made up of 12 protein sub­ within the cell. a random sample of the donor mem­
units, six from each cell. Each group Some of the main intracellular or­ brane. There is one process of material
of six is arranged in a hexagon in the ganelles take part in the manufac­ transfer involving two membranes for
plasma membrane of each apposed ture of membrane components. Mem­ which the way this is accomplished is
cell; the two hexagons lock into each branes are assembled in the endoplas­ beginning to come into focus. That
other to form a channel between the mic reticulum, and oligosaccharides process is endocytosis.
cells. The channel can be held open or are added to membrane proteins in the
closed, but precisely how such control Golgi apparatus. Hence the relations Animal cells obtain most of the small
is achieved is not known. Gap junc­ among many of the organelles are far .£\. molecules they need for growth
tions often interact with one another to from static. For example, there is a either by synthesizing them or by im­
form a raft, or a large group of junc­ continual transfer of membrane from porting them from the blood. The
tions, on the cell surface. The aggre­ the endoplasmic reticulum to the Gol­ imported molecules are usually trans­
gate size of the rafts and their confine­ gi apparatus and from there to the ferred across the plasma membrane by
ment to the membrane regions be­ plasma membrane. The transfers are specific protein channels or pumps.
tween two cells make it likely that probably always mediated by phos­ There are some essential nutrients,
gap junctions are relatively motionless pholipid vesicles. however, that for one reason or anoth­
within the liquid bilayer. Such continual movements of mem­ er cannot be so easily absorbed.
Until this point I have carefully brane material, as well as the mergers For example, cholesterol (which is
avoided any detailed discussion of the and dissociations of vesicular mem­ needed for the synthesis of mem­
many membranes in addition to the branes that accompany the movement, branes) and the ferric ion (an iron atom
plasma membrane that are found in raise anew the question of membrane carrying three positive charges, which

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is needed for the synthesis of the large, protein (LDL) that is some 200 ang­ ferent strategy to obtain the nutrients
pigmented molecules called cyto­ stroms across. Ferric ions in blood it requires.
chromes) both circulate in the blood are bound inside a large carrier pro­ The current picture of how such nu­
as large complexes. Cholesterol circu­ tein called transferrin. Both LDL and trients enter the cell began to emerge in
lates in the form of cholesteryl esters, transferrin are much too large to pass 1964 with the work of Thomas F. Roth
which make up the hydrophobic core through a small channel or pump, and and Keith R. Porter, who were then
of a particle called low-density lipo- so the cell must adopt a radically dif- at Harvard. They were studying how
growing oocytes (egg cells) of the mos­
MICROVILLI quito build up the oocyte's yolk. Ex­
APICAL SURFACE amining thin sections of oocytes under
the electron microscope, they found
that the yolk precursor is bound to the
plasma membrane of the oocyte at
sites where the membrane is indented
and appears to have a thick, dark coat
of material on the side facing the cyto­
plasm. The sites are called coated pits.
In the same thin sections of the oocyte
Roth and Porter also saw vesicles in­
side the cell that were full of yolk pre­
COATED VESICLE
cursor and had thick coats on their
outer surface. They called these struc­
tures coated vesicles. The coated vesi­
cles arise when coated pits bud into the

SHEDDING OF CLATHRIN COAT

cell; they are intermediates, inside the
DESMOSOME

�:,
oocyte's cytoplasm, in the transfer of

- '�� yolk precursor from the cell exterior to

the large yolk granules stored inside
GAP JUNCTION -

I �� . I­
the oocyte.
More recent work by Richard G. W.
EXOCYTOSIS '� Anderson, Michael S. Brown and Jo­
seph L. Goldstein of the University of
Texas Health Science Center at Dallas
on the uptake of LDL and by many
other groups, including my own, on the
uptake of transferrin and other large
BASOLATERAL SURFACE
molecules has by now drawn a fairly
EPITHELIAL CELL and the adjacent parts of its two nearest neighbors are depicted sche­ coherent picture of the early stages of
matically. Such cells line the gut and form dividing layers in other internal organs; in the endocytosis initiated by coated pits.
gut they form a leakproof barrier between the gut and the blood. The seal is effected by the On the outer surface of most growing
tight junction, which also separates the apical surface facing the gut from the basolateral
animal cells there are specific protein
surface facing the blood. Below the tight junction is a desmosome, which welds the two
receptors for LDL, for transferrin and
adjacent cells together, and below the desmosome is a gap junction, which allows small mol­
for other large imported molecules.
ecules to pass from the cytoplasm of one cell directly into the cytoplasm of the adjacent cell.
Nutrient material in the gut can cross the epithelial sheet only if it is first absorbed into an
As the receptors diffuse across the sur­
epithelial cell. Some macromolecules can be taken up by endocytosis. The endocytic vesicle face of the cell they can bind LDL
can then discharge its contents into the bloodstream by exocytosis on the cell's basolateral or transferrin.
surface. The apical membrane and basolateral membrane have different sets of proteins. When an LDL or transferrin recep­
tor encounters a coated pit, it enters
the pit. Other proteins in the plas­
CYTOPLASM CYTOPLASM
ma membrane, however, are excluded
from the pit, which thereby acts as a
molecular sorting device. In about a
minute the coated pit has reached its
full diameter of about .3 micrometer.
The pit then invaginates and breaks

IONS,
away from the plasma membrane
A MINO ACIDS, "'-;"---l into the cytoplasm, where it forms a
SUGARS, .... coated vesicle. The mechanical force
NUCLEOTIDES driving the process is assumed to be
provided by the coat on the cytoplas­

�","",,"·-'-..,,-1'h\
mic side of the pit.
PROTEINS,
NUCLEIC ACIDS

� O
nce the coated vesicle has formed
)I� INTERCELLULAR in the cytoplasm it sheds its coat
1. � SPACE in a few seconds. Then two things hap­
pen. The vesicle fuses with an intra­
GAP JUNCTION between two apposed epithelial cells is made up of two hexagonal studs
(gray), each embedded in the membrane bilayer of one cell (blue spheres with tails at­ cellular organelle called an endosome
tached); the two studs are pressed together in the gap between the cells. Ions, amino acids, and the acidity inside the endosome is
sugars, nUcleotides and other molecules smaller than about 20 angstroms in diameter can then increased to apH of about 5. The
pass through the junction, but proteins, nucleic acids and other larger molecules cannot. acidic environment causes LDL to fall

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SUCCESSIVE STAGES in the formation of a coated vesicle are membrane. The pit deepens (top right), the outer membrane of the
shown in a series of electron micrographs. The shallow indentation cell closes behind the pit (bottom left) and the pit buds off to form a
in the plasma membrane of a developing chicken oocyte (top left) coated vesicle that carries the lipoprotein molecules into the cell
is a coated pit; it holds many particles of a lipoprotein gathered (bottom right). The micrographs were made by M. M. Perry and
from the external environment of the cell. A coat of c1athrin mole­ A. B. Gilbert of the Agricultural Research Council's Poultry Re­
cules can be seen just under the pit, on the cytoplasmic side of the search Centre in Edinburgh. The enlargement is 135,000 diameters.

off its receptor and the ferric ions to tein components of the two mem­ a lattice of a large, fibrous protein she
pop out of transferrin. By unknown branes would quickly become identi­ named clathrin. Such coated vesicles
processes the receptors for LDL and cal. Such mixing does not take place, also carry receptors, the ligand mole­
for transferrin (the latter with its li­ however, because the coated pits select cules attached to the receptors and a
gand, transferrin, still attached) are re­ only certain proteins from the plasma variety of other proteins that could
cycled to the plasma membrane. At membrane for transfer into the cell. It mediate the interaction of clathrin
the same time the LDL, the ferric ions is thought the same set of membrane with the receptors. Coated vesicles are
and other contents of the endosome proteins, now residing in the endo­ generated not only by the plasma
are transferred to lysosomes, again by somal membrane, is cycled back to membrane but also by intracellular
vesicular transport. The lysosome is a the plasma membrane by a similar se­ organelles such as the Golgi appara­
primitive digestive organelle, and it lective process. This selective transfer tus. Hence there is hope that the sort­
degrades the LDL, thereby liberating of membrane by coated pits may ex­ ing mechanism may soon be clarified.
cholesterol to serve the needs of the plain how the integrity of numerous
cell. Note that at this stage both the
cholesterol and the ferric ions must
distinct membrane compartments can
be maintained in spite of continual T he picture of the plasma mem­
brane emerging from this work is
still be transported across at least traffic among them. Note also that dur­ that of a lipid bilayer spanned by a
one membrane, namely the lysosomal ing the endocytic cycle the topology host of different proteins. Some of
membrane, in order to reach their des­ and asymmetry of the membrane are them simply catalyze the transfer of
tinations within the cell. always maintained. small molecules across the bilayer, and
The endocytic cycle initiated by The understanding of how the coat­ they have a globular structure. Others
coated pits gives a dynamic picture of ed pit selects proteins from the plasma have only a single hydrophobic helical
a cell. At any instant about 2 percent of membrane is admittedly incomplete. segment that holds them in the mem­
the surface of a cell growing in culture Nevertheless, it has been greatly ad­ brane; some of the helical proteins are
is taken up by deepening coated pits. vanced by structural studies of the receptors that bring large molecules
Given such a large flux of membrane closely related coated vesicles. In 1976 into the cell. Whereas all, or almost all,
from the plasma membrane through Barbara M. F. Pearse of the Laborato­ of these molecules are free to diffuse
the endosomal compartment and back ry of Molecular Biology isolated coat­ around in the liquid bilayer, there are
again, one might expect that the pro- ed vesicles and showed that the coat is other structures such as the gap junc-

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tions and the tight junctions that re­ cussed. Since they make up the inter­ growth, in which cell multiplication
main relatively static. In contrast there face between a cell and the rest of the and migration can become uncon­
is also the highly dynamic movement organism, they must be involved in trolled. Although a molecular under­
of the membrane during the endocyt­ the movement of cells and in how the standing of such processes is yet to be
ic cycle. movement is directed during growth achieved, current knowledge of the
Plasma membranes take part in and development. The plasma mem­ structure of membranes is a major step
many cellular functions I have not dis- brane also plays a role in cancerous in that direction.

CHOLESTEROL

LDL RECEPTOR TRANSFERRIN

CLATHRIN RECEP TOR

LYSOSOME

GENERALIZED CYCLE of endocytosis and exocytosis is shown with an endosome already bearing receptors from previous cycles
in four stages. Ferric ions in transferrin molecules and cholesterol of endocytosis. The released ferric ions and LDL are transferred to
in particles of low-density lipoprotein (LDL) bind to receptors in a lysosome. A vesicle is also shown budding away from the endosome
the plasma membrane. The receptors bearing transferrin and LDL (3). The vesicle, bearing empty LDL receptors and iron-free trans­
diffuse into a coated pit, which somehow blocks the entry of other ferrin still attached to its receptor, then fuses again with the plasma
kinds of membrane proteins (1). After a pit buds into the cell and membrane, and the receptors enter another cycle of endocytosis.
becomes a coated vesicle the dathrin coat is shed, and increasingly In the lysosome cholesterol is released from the LDL; ferric ions
acidic conditions begin to release LDL from its receptor and the and cholesterol are transported to other parts of the cell (4). The
ferric ions from the transferrin (2). The liberated vesicle then fuses asymmetry of the membrane is maintained throughout the cycle.

108
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 Grandmothers Secret
SHE never let on to any of us mother to bed and sat down to talk professionals helping to regain the
that anything was wrong. Years of to us. From the look on her face, sense of life before the specter of
caring for us had urged her to I knew it was bad news, and death can win a psychological
protect our feelings. There had I suddenly hated her for being victory. Their message is simple
always been tough times before, the one to shatter our secure and concerned. Life isn't over
but with faith and luck, we'd feeling of family. when you discover you have can­
endured. Grandmother must have Grandmother had cancer. cer. As long as there is life, it
felt we would weather this too. There would, of course, be treat­ should be lived. They encourage
She took the bus to go shop­ ments, but in the end the cancer the restrengthening of the attitude,
ping early on Wednesday the first could claim her more easily than the first victim in the battle against
week of April. When she returned, not. It was this inevitable message cancer. Cancer Care also directs
everything was destroyed. It was as that had the effect of making her the patient and family in obtaining
if every last bit of energy, every feel dead already. Mrs. Johnston information about services that
ounce of strength had been spared us nothing. She had always are available, easing the burden
drained. That weathered, beautiful seemed strong and fair, and this when the mind is still reeling from
old woman looked like she'd lost a was a new side of her that we were the diagnosis.
fight before it started. seeing. She had never seemed,
Mrs. Johnston, from across however, more capable than she And, when my Grandmother
the street, stopped by like she had did now. The shock would be was gone, they didn't desert us.
every afternoon for a cup of coffee. weeks in coming, she explained. They kept in touch, helping
She and Grandmother had been For it was not only Grandmother through the loss that dragged at us
friends for years and had shared who would have to live with this so painfully.
their stories and memories out on new knowledge, but us, her family. Just before my Grandmother
the back porch as they watched She would need us like never left us, she called me in to talk. She
the spring approach. Now she before, and yet we would feel as was weaker and talked slowly as
stopped just inside the door and weak as she with the weight of this she told me the words that would
looked at her close friend's face. terrible disease. We would, she guide my life. "Take nothing for
She took command immediately. explained, all be affected. granted. Both the good and the
Grandmother had refused When she left, she gave my bad are necessary, but nothing can
our initial inquiries about her father a number to call. replace purpose in life. Not char­
sudden depression. Mrs. Johnston Grandmother died, as we all ity, not good intenti.ons, and not
moved her to the back porch and do, from one cause or another. medicine:' Then she took my hand
commanded coffee as she care­ But in those last months of her life, and told me what she had learned
fully guided her through the back she lived, I think, more than she from the people at Cancer Care
kitchen. had ever before. The number Mrs. that had made her life easier. "Uve
1\vo hours later, the sun was Johnston had given my father was life to the fullest:'
lost and they still hadn't returned. for Cancer Care. I waited for more, but that
We were hopeless as a family. was it. And as I remembered the
Something was obviously seri­ The people at Cancer Care things the people at Cancer Care
ously wrong and none of us could provide a most important tool in had done, and the time they'd
bring ourselves to talk about it. the battle against cancer. They spent with my Grandmother, I
And the desire to help, to do counsel cancer patients and their realized that that was exactly what
something, made the helplessness families, helping them regain their they'd helped us do.
even more acute. When Mrs. inner strength to deal with the days
Johnston returned, she put Grand- ahead. They are honest, caring

CANCER CARE
people helping people
Cancer Care, Inc., 1180 Sixth Avenue, New York 10036, (212) 679-5700

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