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Dynamic, yet structured: The cell membrane three decades after the Singer–Nicolson model
si * 
**
*Department of Biophysics and Cell Biology and
Cell Biophysical Research Group of the
Hungarian Academy of Sciences, Research Center for Molecular Medicine, Medical
and Health Science Center, University of Debrecen, H-4012, Debrecen, Hungary;
Department of Immunology, Loránd
Eötvös University, H-1117, Budapest, Hungary;
¶Institute of Biochemistry, Biological Research
Center, Hungarian Academy of Sciences, H-6701, Szeged, Hungary; and
||Metabolism Branch, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20892-1374
Contributed by T. Farkas, April 29, 2003
Abstract
The fluid mosaic membrane model proved to be a very useful hypothesis in explaining many, but certainly not all, phenomena taking place in biological membranes. New experimental data show that the compartmentalization of membrane components can be as important for effective signal transduction as is the fluidity of the membrane. In this work, we pay tribute to the Singer–Nicolson model, which is near its 30th anniversary, honoring its basic features, "mosaicism" and "diffusion," which predict the interspersion of proteins and lipids and their ability to undergo dynamic rearrangement via Brownian motion. At the same time, modifications based on quantitative data are proposed, highlighting the often genetically predestined, yet flexible, multilevel structure implementing a vast complexity of cellular functions. This new "dynamically structured mosaic model" bears the following characteristics: emphasis is shifted from fluidity to mosaicism, which, in our interpretation, means nonrandom codistribution patterns of specific kinds of membrane proteins forming small-scale clusters at the molecular level and large-scale clusters (groups of clusters, islands) at the submicrometer level. The cohesive forces, which maintain these assemblies as principal elements of the membranes, originate from within a microdomain structure, where lipid–lipid, protein–protein, and protein–lipid interactions, as well as sub- and supramembrane (cytoskeletal, extracellular matrix, other cell) effectors, many of them genetically predestined, play equally important roles. The concept of fluidity in the original model now is interpreted as permissiveness of the architecture to continuous, dynamic restructuring of the molecular- and higher-level clusters according to the needs of the cell and as evoked by the environment.
Advanced Cell Biophysical and Molecular Biological Methodology Provides Quantitative Data on the Static and Dynamic Organization of Membranes
Membrane dynamics, i.e., the ever changing mobility and proximity relationships of lipid and protein molecules in the plasma membrane, have a significant impact on essential cellular processes, such as activation, ligand-receptor recognition, antigen presentation, intercellular interactions (e.g., between target and killer cells), etc. Quantitative measurements of membrane dynamics are possible with fluorescence recovery after photo-bleaching (13, 14), single-particle tracking techniques (8, 15, 16), and optical trapping by laser tweezers (13, 17, 18). Fluorescence correlation spectroscopy, a method with tradition in the study of reaction kinetics and molecular interactions in solution (19, 20), also has been applied to the study of cellular systems recently (21, 22). The method allows the determination of absolute molecular concentration, mobility, and comobility in small, confocal volume elements of living cells (23). Confocal laser-scanning microscopy (24) at the verge of its resolution limits proved to be successful in determining the uneven cell-surface distribution of various antigens. Scanning near-field optical microscopy (NSOM), a method ideal for assessing localization of membrane proteins at the resolution of several tens of nanometers, also has been gaining space in investigating the cytoplasm membrane (25–28), although, as Edidin (29) points out, "while NSOM promises much, its application to biology is about where electron microscopy was 40 or 50 years ago." These methodologies supported by digital image processing add valuable information to the dynamic data about the spatial distribution and compartmentation of membrane constituents. In general, these approaches provide evidence for the domain-like distribution of lipids and proteins in biological membranes (17, 30, 31).
Restrictions in the lateral mobility of both lipid and protein components were studied extensively by using the fluorescence-recovery-after-photobleaching technique, measuring the diffusion of fluorescently labeled membrane components from non-bleached areas into a small, bleached spot. Lateral diffusion parameters of MHC molecules (9) were highly dependent on the bleached-spot size. Because diffusion rate in a lipid bilayer is expected to be independent of this size, one plausible explanation is the mosaic-like domain structure of the biological membranes that restrict the barrier-free path of proteins and can be partly responsible for the clustered arrangements of membrane proteins.
Single-particle tracking follows the "random walk" of a gold
particle fixed to a cell-surface protein. For the transferrin receptor and
E-cadherin, a barrier-free path of 
400 nm was determined
(8), whereas for wild-type and
cytoplasmatically truncated mutant class I MHC, 600 and 1,700 nm were
measured, respectively (13),
indicating that, for membrane-spanning proteins, the barrier-free path is in
the same range and that barriers to the "free" diffusion are
present 2–3 nm below the membrane bilayer. As shown in
Fig. 1, cytoskeletal elements
and intracytosolic molecules with functional connections to cell-surface
receptors have the capacity either to slow down or to completely stop the
lateral motion of transmembrane proteins.
|
Fluorescence Resonance Energy Transfer (FRET) Highlights Nanometer-Scale Associations in the Cell Membrane
It has been suggested that membrane proteins can be codistributed
nonrandomly, and this nonrandom yet dynamic codistribution pattern even may be
controlled genetically
(32–35).
This assumption has been supported by a significant amount of experimental
data (36,
37). A major asset in studying
these codistributions was the application of FRET to cellular systems. In
FRET, an excited fluorescent dye (donor) donates energy to an acceptor dye if
the separation distance between them is 1–10 nm. In the 1970s,
cell-surface lectins were the first to be investigated by FRET
(38,
39). Since the early 1980s,
more systematic and better established data acquisition and evaluation methods
of FRET were introduced in flow cytometry
(35,
40). A quantitative method was
introduced in digital fluorescence microscopy that exploited the differences
in photobleaching kinetics of donor dyes in the presence and absence of
acceptors (36,
41). Recently, a new method,
based on systematic and normalized FRET measurements between individual
receptor pairs yielding a receptor map by triangulation, has been introduced
to describe the exact two-dimensional topology of receptor clusters
(7,
37). The homo- and
heteroassociations of MHC class I and II
(42), the IL-2 receptor
-subunit and intercellular adhesion molecule 1
(43–45),
MHC molecules and transferrin receptors
(46), CD4 and CD8 antigens
(47,
48), the T cell antigen
receptor (TCR)/CD3 complex
(49), tetraspan molecules
(CD53, CD81, CD82) and CD20 with MHC class I and class II
(50), the three subunits of
the multisubunit IL-2 receptor
(37), the tumor necrosis
factor receptor (51), Fas
(CD95; ref. 52), and many
others have been analyzed in detail. Many receptors were found to be oligomers
preassembled without ligand binding, including tumor necrosis factor receptor,
Fas, and TCR. Results for the IL-2 receptor indicated that its subunits are
preassembled in T cells and do not require cytokine-induced aggregation. This
colocalization was modulated significantly by binding of relevant ILs. In
addition, there is evidence that the IL-15 receptor -subunit, which
shares the 
- and 
-subunits with IL-2R, also can form
preassembled supramolecular structures with IL-2R and the
"common" -chain
(53–55).
These data (37) have
challenged the frequently applied paradigm that multisubunit receptors are
assembled under the influence of their specific ligands and support an
alternative model in which preassembled receptor clusters facilitate faster
and stronger biological responses, because there is no need for lateral
diffusion of receptors to associate.
Electron Microscopy and Scanning-Force Microscopy Reveal Submicrometer Clusters of Membrane Receptors
FRET measurements detect molecular associations in the 1- to 10-nm range.
Combined application of electron and scanning-force microscopy made possible
the discovery of a new, higher hierarchical level of receptor clustering in
lymphoid cells (36). The
distribution of ImmunoGold labels attached to receptors showed a nonrandom
pattern, differing from the Poisson distribution assumed for randomly
scattered molecules. The method also was used under near-physiological
conditions, where the gold particles were detected with scanning-force
microscopy by using tapping mode on hydrated samples
(36). The observation that
nanometer-scale islets of MHC class I molecules in the cell membrane are
organized into micrometer-sized "island groups" was extended to
MHC class II (56) and to the
IL-2 receptor -subunit and the transferrin receptor
(24). Sequential application
of different-sized gold labels targeted to MHC classes I and II also revealed
successively that positive FRET data did not necessarily mean that each
receptor was homo- or heteroassociated in a large population. The degree of
association for MHC class II to MHC class I was 66%, but only 25% of MHC class
I molecules were in the molecular vicinity of MHC class II
(56).
Besides establishing the nonrandom distribution of receptors, ImmunoGold labeling also provided for estimating the average size of higher-order molecular clusters (or island groups) (24). These were in the range of 400–800 nm for various receptors, in good correlation with mean barrier-free paths reported earlier (8, 13). Confocal laser-scanning microscopy of fluorescently labeled, live, and fixed cells followed by surface reconstruction and spatial autocorrelation analysis confirmed the existence of such receptor clusters with sizes essentially equal to those deduced from electron microscopy (24).
Lipid Rafts: The Functional Equivalent of Receptor Islands?
Numerous studies directed at the plasma membrane have provided evidence for
the existence of distinct domains in the submicron range
(24–26,
36,
56–60).
Paralleling these observations, the term "lipid rafts" was coined
based on studies of epithelial cell polarity and gained widespread popularity
in the past years (11).
Biochemical analysis suggested that rafts consist of cholesterol and
sphingolipids in the exoplasmic leaflet of the lipid bilayer and cholesterol
and phospholipids with saturated fatty acids in the endoplasmic leaflet
(61). They are surrounded by
more fluid membrane domains, which are abundant in unsaturated fatty acids
(62). Polyunsaturated
phosphatidylcholines and phosphatidylethanolamines
(63) including ethanolamine
plasmalogens were detected in rafts by quantitative electrospray ionization
and mass spectrometry (64),
probably reflecting a regulatory mechanism that offsets the rigidifying effect
of cholesterol (63). In
addition, 18:1 and 22:6 phosphatidylethanolamines and ethanolamine
plasmalogens are prone to form nonbilayer phases
(65,
66), and the association of
soluble proteins (such as G proteins) to membranes depends on the propensity
of reverse hexagonal-phase areas
(67). This observation
highlights the possible role of lipid rafts in signal-transduction processes.
Isolating lipid rafts as detergent-resistant membrane domains, followed by
Western blotting, indicated that rafts indeed are efficient concentrators of
various proteins, many of them active in cell signaling. Among these were
glycosylphosphatidylinositol-anchored proteins
(68), cholesterol-linked and
palmitoylated proteins such as Hedgehog
(69), Src-family kinases and
-subunits of heterotrimeric G proteins
(70), cytokine receptors
(71), and integrins
(72).
The question is how these biochemically identified, detergent-resistant
membrane domains correspond to the observed confinement of membrane proteins.
As Jacobson and Dietrich (73)
pointed out, "... the nature of the in vivo correlate of such
detergent-resistant membranes remains enigmatic. In principle, microscopy
should be able to determine whether the postulated rafts exist."
Recently, it has been shown that indeed microscopic equivalents of rafts, or,
rather, aggregates of rafts, can be detected by using high-resolution confocal
microscopy and that their disassembly by depletion or in situ
complexation of cholesterol not only destroys their morphology
(24) but also impairs their
signaling capabilities; for example, in T cells, it hinders Stat5 and Stat3
phosphorylation via the IL-2 receptor
(71). Based on the notion that
rafts essentially are membrane units formed from transport vesicles fusing to
the membrane, one would expect their size to be very small
(59). In photonic force
microscopic experiments, it was determined that raft size is <50 nm in
diameter (74), representing
3,500 sphingolipid molecules. This indicates that membrane patches
observed in fluorescence microscopy, bearing raft marker proteins and/or
lipids, probably are aggregates of these basic building blocks. In some
instances, these larger aggregates are not observed in resting cells
(75,
76) and can be seen only upon
crosslinking the "unit rafts"
(75). In other cases, cells in
their native state present surface patches of submicrometer size, identifiable
as rafts based on their composition
(24,
77).
Rafts Are Dynamic Structures Reshaped as Function Requires
A few years ago, little was known about the stability and lifespan of lipid rafts in living cells. It appears now that, compared with the relatively stable nature of phases in artificial bilayers, lipid rafts in cells are relatively short-lived. As Edidin points out in a recent review (78), "... domains are now thought to be smaller and less stable then they were in 1992." Lipid probes with saturated chains on average spend 13 ms in one domain (79); the average lifetime of stable domains is found to be on the scale of tens of seconds (10). Pulsed EPR measurements indicate a very fast exchange rate between protein-rich and bulk domains in the membrane, reaching residency times as low as 15 µs (80). This possibility of rapidly changing composition and location in the membrane, as well as the ability to form aggregates of various sizes, easily can account for the dynamic regulatory role lipid rafts play in various signaling processes. Such a function has been established for receptor tyrosine kinases (27) and for immune receptors such as the TCR (81) and the IgE receptor (82, 83).
The first step in immunoreceptor signaling is represented by
ligand-dependent receptor aggregation, followed by receptor phosphorylation by
tyrosine kinases of the Src family. Lipid rafts have been identified as
platforms wherein signal transduction molecules may interact with the
aggregated immunoreceptors. Multichain immune recognition receptors such as
TCR (84) and Fc
RI
(83) use common mechanisms by
which lipid rafts assist in the initiation of signaling.
The onset of T cell activation is associated with the formation of the
so-called "immunological synapse"
(85) between T cells and the
cells that they are recognizing. This synapse starts with the initial
clustering of receptors and promotes the centralized accumulation of TCRs that
has been termed the "central supramolecular activating complex"
with a corresponding peripheral ring, consisting of lymphocyte
function-associated antigen 1 (LFA-1) ligands
(86). The surface components
of antigen-presenting cells are also integral to these clusters;
MHC–peptide complexes are found in the central supramolecular activating
complex, whereas intercellular adhesion molecule 1, the LFA-1 counterreceptor,
is concentrated in the peripheral supramolecular activating complex.
Initially, the TCRs are not necessarily engaged in the center, but as
cell–cell interaction develops, they translocate from the periphery into
the center of the synapse (87,
88). According to the serial
triggering model, in this manner, very few peptide-presenting MHC molecules
can activate a high number of TCRs
(89). It appears important in
terms of the interaction that palmitoylation of the membrane-proximal
cysteines of CD4 and the association of CD4 with Lck contribute to the
enrichment of CD4 in lipid rafts
(90) and that, furthermore,
K+ channels also reside in rafts in the molecular vicinity of TCR
(91). The structure of the
CTL–target cell contact is similar to that observed between T cell and
antigen-presenting cell, a ring of adhesion proteins surrounding the inner
signal molecule domain. Lytic granule secretion occurs in a separate domain
within the adhesion ring (92).
As for the spatiotemporal coordination of signaling by the high-affinity IgE
receptor FcRI, lipid rafts first concentrate Lyn protein kinases while
excluding the FcRIs from these domains. Upon crosslinking FcRIs by
the antigen, the receptors rapidly translocate into the lipid rafts followed
by their phosphorylation and the subsequent recruitment of Syk and PLC
into these domains (93). The
latter process also involves accumulation of actin cytoskeleton to the active
domains (82).
A recent attempt to repeat the classic experiment of Frye and Edidin (94) with currently available technologies provided interesting data underlining the dynamism of membrane domains. Cells labeled with different fluorescent antibodies were fused with each other. Near-field scanning optical microscopic and parallel FRET studies revealed that intermixing of micrometer-scale protein clusters started right after cell fusion, but there was a delay of about 20 min in the intermixing of nanometer-scale protein associations (28), which clearly indicates the hierarchy of protein associations (Fig. 2). Although these experiments corroborate the existence of protein clusters, they emphasize their dynamism, which may be important for rapidly reshuffling protein interactions.
|
Static and Dynamic Factors Organizing Membrane Domains
The physical and chemical forces giving rise to membrane domains are under intensive investigation (2, 57). One presumes that several intracellular and extracellular constraints and forces influence the size and distribution of these clusters, one of them being the cholesterol content of the membrane area in question (11, 95), and changing the cholesterol composition of the cell membrane alters the association pattern and signaling properties of various molecules (71, 95).
Recently, it was proposed that lipids tend to adopt a super-lattice distribution in fluid-mixed bilayers and distribution of phospholipids in these structures is determined by the molecular shape and the charge of the head group (96, 97). These super-lattice structures do not cover the whole membrane area; rather, they are in dynamic equilibrium with areas in which lipids are distributed randomly. The presence of proteins can modify these structures by depleting or attracting certain lipid species because of similarities or differences in molecular shapes. However, fatty acid and polar head group composition of phospholipids (96), as well as the thermotropic and lamellar- to nonlamellar-phase transitions, are controlled precisely in a way that overall fluidity is reached below body temperature. Molecular architecture of certain phospholipids (98) and proportion of nonbilayer-forming lipids (66) may contribute to this phenomenon. Remarkably, the liquid-ordered- to liquid-disordered-phase transition temperature of rafts proper is 13–15°C above (99) the main transition temperature of membranes (100) because of the high cholesterol and sphingomyelin content. Under pathological conditions such as neurodegenerative diseases, this balance is upset.
Lipid rafts often are looked at as structures originating solely from
lipid–lipid interactions. One should not, however, overlook the fact
that proteins and protein–lipid interactions could be equally important
in the formation, maintenance, and dynamics of these domains. In fact, one can
imagine the basic unit of a raft as a single protein molecule surrounded by
lipids that are especially suitable as its environment regarding polarity and
steric complementarity. In addition to the classic investigations
(101), where very precise
predictions were given about the membrane-spanning -helices, recent
data also suggest that the exact composition and nature of -helical
structures will influence heavily how and in what phospholipid environment
this polypeptide chain can be hosted, if at all
(102). This alone would be
enough to account for protein patterns in cell membranes that are predestined
genetically, as we have predicted decades ago
(32). The primary and
secondary structure of proteins newly synthesized, together with the sorting
capabilities in vesicular transport, can easily determine which proteins will
be embedded into a certain lipid environment and which other proteins will be
their immediate neighbors. For example, it has been demonstrated that the
transmembrane domain of CD40
(103) and influenza
hemagglutinin (104)
determines their partitioning into lipid rafts.
On a similar note but looking at the dynamic side, changes in the structure of proteins [a most evident example being those occurring after their interaction with other proteins or those generated by changes in membrane potential (105)], as well as changes in the constitution or thickness of the various lipid regions, can easily cause reshuffling of the components of lipid rafts so that the best steric/energetic stability is achieved again (106).
The strength of interaction between proteins and their immediate lipid environment is well characterized when lymphoid cells with labeled MHC molecules are fused (28). MHC class II molecules from the two cells did not intermix even after 80 min and maintained their monomeric behavior. It was proposed that the small size of the microdomain allowed such a strong interaction with the membrane-spanning parts of the protein molecule that the cohesive forces prevented the fusion of these microdomains. Interestingly, class II molecules did intermix with class I molecules of the other cell. MHC class I probably was accommodated in larger rafts, which could incorporate the small rafts of class II molecules in their entirety.
As for the assembly and maintenance of protein clusters, the internalization-recycling machinery is one important candidate "force": proteins are recruited to sites of endosome formation, which gives rise to protein associations (107, 108). S—S bonds between integral membrane proteins were implicated in the case of human killer cell-activating receptors expressed in the plasma membrane of natural killer cells as multimeric complexes (109). Partitioning of covalently linked, saturated acyl chains into liquid-ordered phase domains is likely to be an important mechanism for targeting proteins to rafts, whereas prenylated proteins tend to be excluded from there (110). Thus, even without direct protein–protein interactions, preferential accumulation of certain proteins in a lipid domain may induce homoor heteroassociation as well as formation of micrometer-sized protein clusters (Fig. 3).
|
Do We Need a New Paradigm?
Recent data that do not fit the S-N model can be summarized as follows: (i) nonrandom codistribution patterns of receptors in the plasma membrane at different hierarchical levels; (ii) quasipermanent molecular contacts to cytoskeletal elements and signal-transducing molecules; (iii) much shorter barrier-free path than expected for unrestricted diffusion; (iv) domain structure of the lipid components of membranes has the capacity to segregate or colocalize membrane proteins; (v) participation of integral membrane proteins in the maintenance of membrane domains suggests that proteins are as important as structural elements as lipids; and (vi) dynamic reorganization of protein elements in membrane domains allows for streamlined cellular responses and is restricted by protein–lipid and protein–protein interactions.
Thus, the straightforward application of the S-N model as a frame of events
is impossible without introducing a new concept. This new concept has the
following attributes emphasizing the colocalization, comobility, and nonrandom
codistribution of a significant number of cell-surface molecules: (i)
the mobility of the cell-surface (transmembrane,
glycosylphosphatidylinositol-anchored, or any other type of) proteins is
restricted by lipid-domain segregation and the length of the free diffusion
pathway covered without bumping into boundaries; (ii) membrane
proteins may colocalize with each other on the 1- to 10-nm scale in a
homologous or heterologous fashion, making the mosaicism of the S-N model
prevalent; (iii) a second hierarchical level of protein clustering
ranging to several hundred nanometers can be observed for many membrane
proteins; (iv) proteins or protein clusters frequently are
accommodated by lipid rafts organized by weak or strong interactions above,
inside, or below the cell membrane; (v) some receptor types (e.g.,
tumor necrosis factor and IL receptors) are in a preassembled supramolecular
formation even in the absence of their physiological ligands and may form a
tighter formation upon ligand binding; (vi) ligand-evoked receptor
aggregations (e.g., epidermal growth factor receptor family) are distinctly
different from preformed oligomers, yet may serve as equally important
amplifying factors of transmembrane signaling; (vii) the smallest
microdomains can be considered modules that accommodate membrane proteins
either alone or in functional oligomers preassembled from subunits, and these
can be the building units of larger signaling domains (such as those formed in
the immunological synapse); (viii) the -helical
membrane-spanning parts of transmembrane proteins are matched in length and
shape by the aliphatic side chains of lipids constituting the membrane domains
that preferentially accommodate them; (ix) the localization of
proteins in different lipid regions of the plasma membrane can be determined
genetically because the amino acid sequence of the transmembrane domain and
sequence-dependent covalent modifications define the possible, specific
lipid–protein interactions; (x) proteins are likely to have an
equally important role in determining the constituents, structure, and
dynamics of membrane domains; (xi) whereas artificial lipid bilayers
tend to spontaneously form segregated structures, the dynamics and specificity
in the living cell membrane are provided by specific protein–protein and
protein–lipid interactions, as well as the targeted and sensitively
regulated nature of vesicular transport processes; and (xii)
identification of the origin and characteristics of microdomains and receptor
assemblies therein may help us understand the immediate past and future of
cells, their activation state, and reactivity. Such signals may carry
diagnostic, prognostic, or even therapeutic values if these nonrandom receptor
patterns can be linked to diseases affecting the different states and/or
altered genetic material of the cell.
In light of the above attributes, we must understand that biological details are far more complicated than the resolving power of a simple model, which describes generalized, uniform behavior of molecules in the membrane. The S-N model is valid, and free diffusion can occur within domain borders, where molecular interactions do not interfere. This means that the emphasis must be shifted from the fluidity to the mosaicism of the S-N model. Mosaicism can restrict free diffusion through one of the following ways: (i) lipid domain structure, (ii) cytoskeletal or other cytosolic interactions, or (iii) homo- and heteroassociations with other integral proteins. These interactions have the capacity to increase the lifetime of an intermolecular encounter, thereby increasing the possibilities for bi- or multilateral interactions, which sometimes simply are called receptor crosstalk. Hence, the overall mobility of molecular elements of the membrane can be accepted with the above restrictions, making the membrane a heavily compartmentalized, quasi-two-dimensional structure, which is more mosaic-like than fluid. In this two-dimensional plane, diffusion, intermolecular forces, the ever changing membrane potential, and extracellular influences can dynamically generate and destroy supramolecular structures. We propose that this new model of the cell membrane be called the dynamically structured mosaic model.
Acknowledgements
This work was supported in part by Hungarian Academy of Sciences Grants OTKA T03783 [GenBank] 1, T03439 [GenBank] 3, TS 040773, TS 044836, T04261 [GenBank] 8, T04306 [GenBank] 1, T04308 [GenBank] 7, and T04350 [GenBank] 9. G.V. is a Békésy Fellow of the Hungarian Ministry of Education.
Footnotes
Abbreviations: S-N model, Singer–Nicolson fluid mosaic membrane model; FRET, fluorescence resonance energy transfer; TCR, T cell antigen receptor.
G.V. and J.S. contributed equally to this work. 
** To whom correspondence should be sent at the * address. E-mail: dami{at}jaguar.dote.hu.
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