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Lipids on the frontier: A century of cell-membrane bilayers

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18. Ford, M. G. et al. Curvature of clathrin-coated pits driven 46. Raposo, G., Tenza, D., Murphy, D. M., Berson, J. F. & Acknowledgements
by epsin. Nature 419, 361–366 (2002). Marks, M. S. Distinct protein sorting and localization to We thank S. Caplan and M. Boehm for critically reviewing the
19. Waters, M. G., Serafini, T. & Rothman, J. E. ‘Coatomer’: premelanosomes, melanosomes, and lysosomes in manuscript.
a cytosolic protein complex containing subunits of non- pigmented melanocytic cells. J. Cell Biol. 152, 809–824
clathrin-coated Golgi transport vesicles. Nature 349, (2001).
248–251 (1991). 47. Sachse, M., Urbe, S., Oorschot, V., Strous, G. J. & Online links
20. Barlowe, C. et al. COPII: a membrane coat formed by Klumperman, J. Bilayered clathrin coats on endosomal
Sec proteins that drive vesicle budding from the vacuoles are involved in protein sorting toward DATABASES
endoplasmic reticulum. Cell 77, 895–907 (1994). lysosomes. Mol. Biol. Cell 13, 1313–1328 (2002). The following terms in this article are linked online to:
21. Dell’Angelica, E. C. et al. AP-3: an adaptor-like protein 48. Wu, X. et al. Clathrin exchange during clathrin-mediated InterPro: http://www.ebi.ac.uk/interpro/
complex with ubiquitous expression. EMBO J. 15, endocytosis. J. Cell Biol. 155, 291–300 (2001). ENTH
917–928 (1997). 49. Wu, X. et al. Adaptor and clathrin exchange at the plasma LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
22. Simpson, F., Peden, A. A., Christopoulou, L. & membrane and trans-Golgi network. Mol. Biol. Cell 14, GGAs
Robinson, M. S. Characterization of the adaptor-related 516–528 (2003). Swiss-Prot: http://www.expasy.ch/
protein complex, AP-3. J. Cell Biol. 137, 835–845 (1997). 50. Goldberg, J. Decoding of sorting signals by coatomer β1-adaptin | γ-adaptin | Arf1 | Arf3 | Eps15 | Eps15R | epsin 1 |
23. Dell’Angelica, E. C., Mullins, C. & Bonifacino, J. S. through a GTPase switch in the COPI coat complex. KIF13A | Rabaptin-5
AP-4, a novel protein complex related to clathrin Cell 100, 671–679 (2000).
adaptors. J. Biol. Chem. 274, 7278–7285 (1999). 51. Collins, B. M., McCoy, A. J., Kent, H. M., Evans, P. R. & FURTHER INFORMATION
24. Hirst, J., Bright, N. A., Rous, B. & Robinson, M. S. Owen, D. J. Molecular architecture and functional model Juan S. Bonifacino’s laboratory:
Characterization of a fourth adaptor-related protein of the endocytic AP2 complex. Cell 109, 523–535 (2002). http://eclipse.nichd.nih.gov/nichd/cbmb/SIPT_Page.html
complex. Mol. Biol. Cell 10, 2787–2802 (1999). 52. Lederkremer, G. Z. et al. Structure of the Sec23p/24p Jennifer Lippincott-Schwartz’s laboratory:
25. Dell’Angelica, E. C., Klumperman, J., Stoorvogel, W. & and Sec13p/31p complexes of COPII. Proc. Natl Acad. http://eclipse.nichd.nih.gov/nichd/cbmb/sob/index.html
Bonifacino, J. S. Association of the AP-3 adaptor Sci. USA 98, 10704–10709 (2001). Access to this interactive links box is free online.
complex with clathrin. Science 280, 431–434 (1998).
26. Peden, A. A., Rudge, R. E., Lui, W. W. & Robinson, M. S.
Assembly and function of AP-3 complexes in cells
expressing mutant subunits. J. Cell Biol. 156, 327–336
(2002).
27. Boehm, M. & Bonifacino, J. S. Adaptins: the final
recount. Mol. Biol. Cell 12, 2907–2920 (2001). TIMELINE
28. Antonny, B. & Schekman, R. ER export: public
transportation by the COPII coach. Curr. Opin. Cell Biol.
13, 438–443 (2001).
29. Bi, X., Corpina, R. A. & Goldberg, J. Structure of the
Sec23/24-Sar1 pre-budding complex of the COPII
vesicle coat. Nature 419, 271–277 (2002).
Lipids on the frontier: a century of
30. Orci, L., Glick, B. S. & Rothman, J. E. A new type of
coated vesicular carrier that appears not to contain
clathrin: its possible role in protein transport through the
cell-membrane bilayers
Golgi stack. Cell 46, 171–184 (1986).
31. Bednarek, S. Y. et al. COPI- and COPII-coated vesicles
bud directly from the endoplasmic reticulum in yeast. Cell
83, 1183–1196 (1995). Michael Edidin
32. Malhotra, V., Serafini, T., Orci, L., Shepherd, J. C. &
Rothman, J. E. Purification of a novel class of coated
vesicles mediating biosynthetic protein transport through Our present picture of cell membranes as their dynamic interplay. However, it is hard
the Golgi stack. Cell 58, 329–336 (1989). lipid bilayers is the legacy of a century’s to capture the dynamic interplay between
33. Presley, J. F. et al. Dissection of COPI and Arf1 dynamics
in vivo and role in Golgi membrane transport. Nature 417, study that concentrated on the lipids and the components of cell membranes. We have
187–193 (2002). proteins of cell-surface membranes. Recent information on the interactions of mem-
34. Hirschberg, K. et al. Kinetic analysis of secretory protein
traffic and characterization of Golgi to plasma membrane work is changing the picture and is turning brane lipids with one another and with
transport intermediates in living cells. J. Cell Biol. 143, the snapshot into a video. membrane proteins, but, until recently, it has
1485–1503 (1998).
35. Huang, F., Nesterov, A., Carter, R. E. & Sorkin, A. not been easy to apply this information to
Trafficking of yellow-fluorescent-protein-tagged µ1 All of the membranes of eukaryotic cells sep- the membranes of living cells. Often, spatial
subunit of clathrin adaptor AP-1 complex in living cells.
Traffic 2, 345–357 (2001). arate functional compartments, but the cell- resolution has been sacrificed for the sake of
36. Waguri, S. et al. Visualization of TGN to endosomes surface membrane — the plasma membrane temporal resolution and vice versa. However,
trafficking through fluorescently labeled MPR and AP-1 in
living cells. Mol. Biol. Cell 14, 142–155 (2002). — is an extreme. It is the frontier between in recent years, new techniques have allowed
37. Puertollano, R. et al. Morphology and dynamics of
clathrin/GGA1-coated carriers budding from the trans-
the cell and its environment. Exploration of us to visualize cell-membrane structure and
Golgi network. Mol. Biol. Cell (in the press). this frontier has revealed its physical and dynamics on scales that match those of stud-
38. Kaether, C., Skehel, P. & Dotti, C. G. Axonal membrane
proteins are transported in distinct carriers: a two-color
functional properties. The plasma mem- ies of model membranes. The next step to
video microscopy study in cultured hippocampal brane is a lipid bilayer, the composition of take is one towards a new integrated model
neurons. Mol. Biol. Cell 11, 1213–1224 (2000).
39. Ahmari, S. E., Buchanan, J. & Smith, S. J. Assembly of
which regulates frontier crossings by mole- of membrane structure and dynamics, that
presynaptic active zones from cytoplasmic transport cules between a cell’s surroundings and its is, towards a model that spans many
packets. Nature Neurosci. 3, 445–451 (2000).
40. Aridor, M., Bannykh, S. I., Rowe, T. & Balch, W. E.
interior, and the properties of the bilayer are timescales and spatial scales. Here, I look
Sequential coupling between COPII and COPI vesicle different from those of any of its components back and discuss the way in which the lipid-
coats in endoplasmic reticulum to Golgi transport.
J. Cell Biol. 131, 875–893 (1995).
alone. bilayer model developed over the past
41. Gaidarov, I., Santini, F., Warren, R. A. & Keen, J. H. Explorers of the cell frontier draw their one-hundred years (TIMELINE). Then, I look
Spatial control of coated-pit dynamics in living cells.
Nature Cell Biol. 1, 1–7 (1999).
resources from the physical chemistry of forward and suggest some elements for a
42. Nakagawa, T. et al. A novel motor, KIF13A, transports pure lipid ensembles, that is, model mem- dynamic model of the plasma membrane.
mannose-6-phosphate receptor to plasma membrane
through direct interaction with AP-1 complex. Cell 103,
branes made in vitro from just one or two
569–581 (2000). kinds of lipid. The data from these simplified Membrane history: cells and models
43. Shiba, Y., Takatsu, H., Shin, H. W. & Nakayama, K.
γ-adaptin interacts directly with rabaptin-5 through its
membranes allow the exploration of more Cell boundaries and cell permeability. To use
ear domain. J. Biochem. (Tokyo) 131, 327–336 complicated cell membranes that are rich in the style of Rudyard Kipling, “In the high
(2002).
44. Volchuk, A. et al. Megavesicles implicated in the rapid
proteins and that contain a bewildering and far off times cells, O best beloved, had
transport of intracisternal aggregates across the Golgi array of lipids. The approach of physical no plasma membranes”. They had only an
stack. Cell 102, 335–348 (2000).
45. Heuser, J. & Kirchhausen, T. Deep-etch views of clathrin
chemistry provides information on how ‘end layer’ — an outer layer of protoplasm of
assemblies. J. Ultrastruct. Res. 92, 1–27 (1985). lipids associate with one another and on unknown composition and properties,

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 PERSPECTIVES

Timeline | A century of cell-membrane bilayers

Langmuir7 publishes a
model of how oil After considerable
molecules are The fluidity of membrane lipids debate10,11, a
Lord Rayleigh, orientated at the begins to be detected by consensus is
Agnes Pockels water/air interface, Danielli and several methods (for a review, reached that cell- The importance of We are awaiting a new model
and many which is based on the Davson6 describe see REF. 14). Lateral and membrane lipids membrane trafficking that integrates the numerous
others begin to experiments of Agnes an influential rotational diffusion of are organized as to the steady-state features of eukaryotic cell
investigate the Pockels but with an membrane model membrane proteins begin to bilayers as plasma-membrane membranes, which have
spreading of oil improved apparatus that integrates lipids be demonstrated in several proposed in structure begins to be emerged since they were first
on water. (BOX 1). and proteins. laboratories13,15–17. REF.19. appreciated32–34,39. characterized.

1880s 1899 1917 1925 1935 1959 1969 1972 1973 1977 1980s 1990s 2003

Overton1 describes a lipid Gorter and Grendel8 Robertson2 argues Data on membrane A domain model is The fact that membrane lipid
barrier between the use Langmuir’s that all cell protein composition and proposed, which and protein domains have
eukaryotic cell cytoplasm methods to infer that membranes have a mobility are fused in the indicates that various cell functions begins
and the outside world. This erythrocyte common structure. fluid mosaic model of cell membranes can be to be appreciated30,36.
work also focuses membranes are membranes19. mosaic rather than
attention on the cell- bilayers. fluid27.
surface membrane as the
membrane that is most
accessible to experimental
study.

which was often described in nineteenth- century BC (BOX 1). In 1917, Irving Langmuir they did not extend straight out from the sur-
century literature as a precipitate1. This end improved Agnes Pockels’ method for measur- face of the water, but were bent7.
layer was explored by physiologists, chemists ing the pressure that is exerted by molecular This work paved the way for the resolution
and morphologists (for a review, see REF. 2). films as they spread on water. In a splendid of the bilayer structure of the plasma mem-
Physiologists characterized the cell surface in paper, he showed that lipids that spread in this brane. The first step in this resolution came
terms of its functions; they measured the ease way form a monomolecular layer on the sur- when Langmuir’s methods for measuring
or difficulty with which migrant molecules face of water. Simple arithmetic gave the area the area per lipid molecule were applied to
and ions crossed the frontier. These physio- per lipid molecule and also showed that the lipid extracts of erythrocyte membranes by
logical measurements showed that fat-soluble hydrocarbon chains of the lipids were flexible; Gorter and Grendel in 1925 (REF. 8). Using
molecules generally crossed the frontier more
easily than water-soluble molecules and ions.
The cell-surface barrier was therefore inferred
Box 1 | Oil spreading on water, Ms Agnes Pockels and the Langmuir trough
to be a lipid of some sort — in the words of
the pioneering study, a “fatty oil” — rich in A Langmuir trough is a simple device for Oil/fat layer Hydrophobic tail
cholesterol and phospholipids1. Later, physi- controlling the spreading of an oil or fat on a
ological and biophysical experiments devel- water surface (see figure). The molecules in
oped this initial model into a combined the film become orientated so that their
hydrophobic tails are in the air and their polar Barrier
chemical and morphological model that
was a layer, just a few lipids thick, which was heads are in the water. A key part of this
Polar head
coated with proteins. In the 1920s and 1930s, device is a method for moving the barrier to
measurements of cell-membrane capacitance cause a defined lateral pressure against the oil
layer. This was Langmuir’s great improvement Water
by Fricke3 indicated that the plasma mem-
on Ms Agnes Pockels’ apparatus (see below).
brane was only 4-nm thick, and measure-
Oil films on water have been used and characterized in many different ways:
ments of the surface tension of many kinds of
• Eighteenth century BC: Babylonians spread oil for divination.
cells by Harvey (see REF. 4 for his 1935 paper
with Danielli, which includes earlier results) • 1770: Benjamin Franklin experimented with the damping of surface waves by spreading olive oil
and Cole5 indicated that the surface was cov- on the surface of an English pond.
ered with proteins rather than being naked • Late nineteenth century: Lord Rayleigh worked on surface tension and received a letter from
lipid. The model was elaborated in a 1935 Agnes Pockels who developed the Langmuir trough in her family’s kitchen. You can read more
review by Danielli and Davson6. about Ms Pockels at the Contributions of 20th century women to physics web site (see Online
links).
Lipid monolayers and membrane structure. • Early twentieth century: Langmuir7 provided detailed explanations of the thickness of oil
Membrane chemistry and physics as we know layers and the orientation of molecules. He developed the Langmuir film balance to measure
them today began with observations of the surface tension.
spreading of oils and fats on water — observa- The diagram and information in this box were provided courtesy of M. Dennin, Department of
tions that go back to Babylon in the eighteenth Physics and Astronomy, University of California, Irvine, USA.

NATURE REVIEWS | MOLECUL AR CELL BIOLOGY VOLUME 4 | MAY 2003 | 4 1 5

PERSPECTIVES

and the resolution that it can obtain. similar to that of olive oil — a more ‘exotic’
However, once a structure that corresponded standard is the viscosity of crocodile fat on a
to a bilayer had been imaged, it became clear warm summer’s day.
that it was not only the plasma membrane It proved harder to characterize the prop-
that had this 75-Å-thick structure and, by erties of membrane proteins than those of
1959, it was being argued by Robertson that membrane lipids. Many of the difficulties
all cell-organelle membranes had a common were encountered because membrane pro-
structure2 (FIG. 1). Even ten years later, though, teins are poorly soluble in water. Studies of
the bilayer was not accepted as the basic struc- erythrocyte membrane proteins11,18 and sur-
ture of cell membranes, and an important veys of proteins that were extracted from vari-
review by Stoeckenius and Engelman10 was ous other membranes led Singer and
devoted to weighing up the evidence for the Nicolson19 to make a crucial distinction
bilayer structure against the possibility that between integral and peripheral membrane
cell membranes were made of discrete, glob- proteins in 1972. This took us to the model
ular subunits. An even later review offered that is still the way most of us see membranes
various models for protein insertion into — the fluid mosaic model (FIG. 2). The mosaic
the bilayer11. However, within a few more is made of proteins that are inserted into the
years, the reinterpretation of older work on fluid, which is the lipid bilayer. The model is
the X-ray diffraction patterns of membranes12 more of a cartoon than a predictive model,
and the accumulation of new evidence on the but it successfully managed to capture and
physical state of membrane lipids13 consoli- integrate diverse experiments on membrane
dated the bilayer model for membranes. physics and chemistry.
Rapidly evolving magnetic resonance meth- The history of the lipid-bilayer membrane
ods — NMR and electron spin resonance — cannot be discussed without commenting on
Figure 1 | The unit membrane concept. This showed that bilayer lipids were in motion the forces that hold the bilayer together. The
figure reproduces work that was published in a
over numerous scales of time and distance, main force that shapes a bilayer from a mix-
paper by Robertson2, in which he both
summarized the available data and used many flexing and diffusing in the plane of the mem- ture of amphipathic lipids is the hydrophobic
new examples to make the point that all cell brane. In short, the bilayer was more like a force20, that is, lipids form bilayers to mini-
membranes have a common structure. In fluid than a solid. This work, which was mize their contact with water. This principle
electron micrographs of osmium-fixed cells, this mainly from the laboratories of McConnell also applies to the insertion of membrane
common structure appears as the well-known and Chapman, is summarized in a contem- proteins into the bilayer — the proteins are
trio of two dark lines separated by a clear region.
porary review14. The review also mentions the usually arranged so that their hydrophobic
Although this structure is hard to resolve in the
images shown, it can be seen by close possibility that bilayer lipids are asymmetrically surfaces are buried in the lipid. These amino-
examination of the originals. Reproduced with distributed — that is, that the two membrane acid sequences are often flanked by charged or
permission from REF. 2 © the Biochemical leaflets have a different lipid composition other polar residues that interact with the
Society (1959). and fluidity — which was first shown to be watery environment of the bilayer surface21,22.
the case for erythrocyte membranes, and In the bilayer membrane model of the
was predicted to be the case for all mem- 1980s, cell membranes were based on a
‘Langmuir’s trough’ (BOX 1), they measured brane bilayers, by Bretscher11. largely fluid lipid bilayer in which proteins
the area occupied by lipids that were extracted Solutes diffuse in a fluid and, in the early were embedded. The bilayer was highly
from a known number of erythrocytes. Then, 1970s, Cone and Poo and Frye and I showed dynamic; lipids23 and proteins24 could flex,
they measured the surface area of whole ery- that some proteins can readily diffuse in lipid rotate and diffuse laterally in a two-dimen-
throcytes and calculated that the lipids of bilayers15–17. The diffusion coefficients indi- sional fluid. The fluid was isotropic, that is,
a single erythrocyte could be accommodated cated that there was an average viscosity for the diffusion of the proteins and lipids was
by a lipid bilayer. After summarizing their the bilayer that was 100-times greater than the random unless it was constrained by the
measurements and calculations for the ery- viscosity of water. The commonplace view cytoskeleton or by the high concentration of
throcytes — or, as they referred to them, now is that the average bilayer lipid viscosity is membrane proteins. The lipids immediately
chromocytes — of six different mammalian surrounding a membrane protein could
species, they concluded that,“It is clear that all affect the function of the protein, which
our results fit in well with the supposition that might be one explanation for the large num-
the chromocytes are covered by a layer of fatty “The commonplace view ber of lipid species (some 500–1,000 different
substances that is two molecules thick”. now is that the average kinds of lipids) that are present in a single
Although Gorter and Grendel made several membrane. There were numerous ideas
experimental mistakes9, the errors cancelled bilayer lipid viscosity is about the coupling of reactions by diffu-
one another out and the authors reached the similar to that of olive oil sion25,26, but often the diffusion measure-
correct conclusion. So, the lipid-bilayer ments were made on a µm scale, when the
membrane was born. — a more ‘exotic’ standard relevant reactions occurred on a scale of 10s
is the viscosity of of Å. The 1980s model captures the complex-
The 1950s to 1980s: fluid membranes. Optical ity of the fluid bilayer and the possibilities for
imaging of membrane morphology had to crocodile fat on a warm molecular interactions in it by diffusion and
wait for the advent of electron microscopy summer’s day.” collision. Although there had been a brief

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 PERSPECTIVES

interest in detecting lipid-phase transitions in a Outside

cell membranes, by 1980 the model largely
neglected the possibility that lipids might not
be randomly distributed in the bilayer and
also understated the degree of local order
that might be possible in membranes.
PAS-1 GP GP
GP
The 1990s: membrane domains. As the fluid
mosaic picture was being assimilated by cell
biologists, another picture was being sketched 3 3
2 7
in which membranes contained patches of 1
2
4.1 1 2
lipids, the composition and physical state of 5
which differed from the average for the bilayer. 6 S … S 4.2 5
This sketch by Jain and White started with
model membranes27, and was followed by a Inside
lot of work on the formation of lipid patches
in model membranes. The lipids were said to
form ‘domains’, which implies that the patches b
are not at equilibrium and so are not as stable
or as long-lived as separated phases, which are
at equilibrium. At first, these experiments
used mixtures of gel and fluid, such as that
shown in FIG. 3, but they evolved to use sys-
tems of immiscible fluid lipids, which are
appropriate models for biological mem-
branes. Some measurements on whole cells
and intact membranes also detected lipid
domains (for examples, see REFS 28,29),
although some cell-membrane domains
seemed to be larger than those of the model
membranes. However, this difference might
be a result of the resolution limits that affect
studies of cell membranes versus model mem-
branes30,31.
Lipid domains were proposed to solve
the problem of sorting and trafficking lipids
Figure 2 | The fluid mosaic membrane of Singer and Nicholson. In contrast to the Danielli and
and lipid-anchored proteins in polarized
Davson membrane model6, which used membrane function to indicate membrane structure, the fluid
epithelial cells32. These molecules are dif- mosaic model19 began with membrane chemistry and proposed function. a | This figure is modified from
ferentially presented on the apical surface one in a review on erythrocyte proteins by Steck41. It is interesting to see that the lipid bilayer is shown only
of morphologically polarized cells, which as two parallel lines and to see the distinction between integral and peripheral proteins. The integral
indicates that the cytoplasmic cell-sorting proteins, which are represented by fruits and vegetables, are inserted into the bilayer. The proteins of the
machinery can recognize them, even though membrane skeleton, which are drawn as boxes and are numbered, have been applied to the inner surface
they are on the inner surface of trafficking of the membrane. Modified with permission from REF. 41 © the Rockefeller University Press (1974). b | This
is a more exuberant version of the fluid mosaic model, which shows the lipids in more detail. Different lipid
vesicles33. The ‘lipid-raft’ model proposed
species are shown in different colours. This figure was created by P. Kinnunen (University of Helsinki,
that lipids that are to be sorted segregate Finland) and was kindly provided by Kibron Inc., Helsinki, Finland.
into a raft, which is rich in cholesterol and
sphingolipids. The entire raft is then rec-
ognized for trafficking either because it
also contains transmembrane proteins or shifted from lipid rafts as trafficking units to Modern times
because the state of the raft lipids is some- lipid rafts as signalling platforms36. In my So, what is missing from our picture of the
how detected by cytoplasmic proteins. opinion, great confusion has arisen from the cell frontier and why does it matter? The first
In 1992, the first, careful test of the raft idea that rafts represent relatively large and missing element is dynamics. We’ve noted
hypothesis by Brown and Rose showed that stable lipid domains that are 10s or 100s of nm that lipids ‘dance to many tempos’; the prob-
a lipid-anchored protein could indeed enter a in diameter. A loose analogy for this mem- lem is therefore to keep track of all the
cholesterol- and sphingolipid-rich lipid brane bilayer picture would be thousands of dancers and to see how they change their
domain, which could be isolated in cold deter- small blocks of butter floating in a sea of heavy dance from one tempo to another (for exam-
gent34. Later work, which was often less careful cream. A more realistic picture, however, ple, from disordered and closely apposed
(see the comments in a recent review35), found might be a mixture of heavy and light cream to diffusing among other lipids, and then to
that many other molecules, such as signalling that is on the verge of blending into a single diffusion in and out of a lipid domain that
kinases, could be isolated in this detergent- fluid, but that is refreshed by new deliveries of persists for a few seconds). Single-particle
insoluble complex and attention therefore one type of cream or the other. tracking methods offer a way to visualize

NATURE REVIEWS | MOLECUL AR CELL BIOLOGY VOLUME 4 | MAY 2003 | 4 1 7

PERSPECTIVES

model. I think that a new plasma-membrane 20. Tanford C. The hydrophobic effect and living matter.
Science 200, 1012–1018 (1978).
model will be the morphologists’ model after 21. Tomita, M., Furthmayr, H. & Marchesi, V. T. Primary
all — a ‘greater membrane’ that takes into structure of human erythrocyte glycophorin A.
Isolation and characterization of peptides and
account not only the bilayer and its embed- complete amino acid sequence. Biochemistry 17,
ded proteins, but also the asymmetry of the 4756–4770 (1978).
22. Killian J. A. & von Heijne, G. How proteins adapt to a
lipid distribution between the two leaflets of membrane–water interface. Trends Biochem. Sci. 25,
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that this asymmetry is used to connect the by deuterium NMR. Science 222, 280–288 (1984).
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Transduction (RG Landes Bioscience Austin, Texas,
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Acknowledgements
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I would like to thank R. A. Cone (Department of Biophysics, Johns
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turnover randomizes membrane molecules; if 15. Frye, L. D. & Edidin, M. The rapid intermixing of cell
access to his file of classic papers in membrane biology, many of
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visual receptor membrane. Nature New Biol. 15, 39–43
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internal reflection microscopy offers a way to the photoreceptor membrane. Nature 247, 438–441 FURTHER INFORMATION
investigate this possibility40. (1974). Contributions of 20th century women to physics: Agnes
18. Fairbanks, G., Steck T. L. & Wallach, D. F. H. Pockels:
A third missing element is the association Electrophoretic analysis of the major polypeptides of the http://www.physics.ucla.edu/~cwp/Phase2/Pockels,_Agnes@
of the cytoskeleton with the bilayer. There is a human erythrocyte membrane. Biochem. 10, 2606–2617 871234567.html
(1971). Michael Edidin’s laboratory:
large amount of literature on this topic, but it 19. Singer S. J. & Nicolson, G. L. The fluid mosaic model of http://www.bio.jhu.edu/Directory/Faculty/Edidin/Default.html
has not been integrated into a new membrane cell membranes. Science 175, 720–731 (1972). Access to this interactive links box is free online.

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