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I. TITLE : The Fluid Mosaic Model Of Cell Membrane Structures


II. INTRODUCTION :
Biological membranes play a crucial role in almost all cellular phenomena. In order to
understand how any biological system function, the detailed molecular composition and
structures of the system must be known. There have been some investigators who impressed with
diversity membrane composition and function and did not intend to make any generalization even
about the gross structures of the membranes. Singer and Nicholson however did not share that
view. They suggest that an analogy is present between membrane and protein structures. Protein
itself shares a uniquely tremendous composition and diverse structures. The generalization based
on this article, in case of protein characters in cell membrane, might be helpful in order to
understand its properties and functions. The valid generalization might exist in protein-lipid
organization in intact membrane. This generalization testing or models brought readers to the
explanation of old experiment and possible new ones.
Singer himself had already examined several model of structural organization in terms
of thermodynamic of membrane system related to available experimental evidence. Based on his
publication, this thermodynamic restriction fit well only with mosaic structures of alternating
globular proteins and phospholipid bilayer, and the two is the only membrane model that
consistent with such restriction and the available data. Since then, much article has been
published that strongly support and extend his fluid mosaic model. Mosaic appears to be fluid or
dynamic, two dimensional oriented viscous solution. Such model proposed is applicable to most
functional membranes such as: plasmalemmal and intracellular membranes (membrane different
organelles; mitochondria, chloroplast). The following article wrote by Singer and Nicholson is
then intended to discuss fluid mosaic model of membrane structures and its applicability to most
biological membrane structure.
III. OBJECTIVES :
This paper is intended to discuss Fluid mosaic model of membrane structures based on
Singer & Nicholson articles, the following points are among the concern of discussion by the
writers:
1. To discuss some thermodynamics of macromolecular, particularly membrane
system, in aqueous condition
2. To discuss properties of protein and lipid on functional membrane
3. To describe detail fluid mosaic model
4. To analyze direct experimental evidence for proposed model
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IV. DISCUSSION
a. Membrane Structures
Thermodynamics of macromolecular system is used because it applies to any
macromolecular system of aqueous environment. Two kinds of non-covalent interaction,
hydrophobic and hydrophilic interaction, present by means of thermodynamic system (require
specific expenditures, in form of kilocalories, of free energy contribution on specific temperatures
in order to be able to transfer molecules). Hydrophobic interaction is a set of thermodynamics
factors that responsible to sequestering/spacing hydrophobic (non-polar residues in the interior)
away from contact with water. While hydrophilic interaction is meant as set of thermodynamic
factors that are responsible for the preference of ionic and polar group for an aqueous
environment. The free energy contribution is primarily important to determine the conformation
that proteins adopt in aqueous solution for placing the models.
Figure 1. Cross section of phospholipid bilayer
Phospholipid bilayer illustrates the combined effect of hydrophobic and hydrophilic
interaction (phospholipid is an amphipathic molecule, asymmetric structures with one highly
polar and highly non-polar end) (Figure 1). Phospholipids are molecules that have two long fatty
acid (lipids-hydrophobic) chains linked to a phosphate bearing groups (readily bond with water-
hydrophilic). Thus phospholipid bilayer is a component of plasma membrane composed of two
layers of phospholipids, arranged with their fatty acid chains pointing toward each other.
Consequences of phospholipids are: gives membrane fluid nature (oil make up of its tails) and
because of the hydrophobic layers, only a very few molecules that can pass through them.
Hydrophilic substances (ion, amino acid, and all polar molecules) cannot pass fatty acid chain
without help. (Krogh, 2011 p: 96). Other types of membrane lipids are also amphipathic and most
of the proteins within membranes have both hydrophobic and hydrophilic regions. In the uid
mosaic model, the membrane is a uid structure with a mosaic of various proteins embedded
in or attached to a double layer (bilayer) of phospholipids (Reece, 2010. p: 123)
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Protein is the most abundant compare to lipid and oligosaccharide. That is why
substantial fraction of this protein might play the role in determining structural function. The
hydrophobic and hydrophilic interaction need to be maximized, thus the classical model which
minimizes the interaction was rejected.
b. Properties of membrane component
Important protein bound membrane, peripheral and integral protein is discussed here.
Peripheral protein characters are: require mild treatments to molecularly disassociate them from
intact membrane, disassociate freely in lipid, and relatively soluble in neutral aqueous, of it
disassociate state. The characters suggest that this type of protein bound weakly by non-covalent
interaction and associate weakly with lipid (ex: cytochrome mitochondrial membrane). Integral
proteins, the most abundant, characters on the other hand are: need much more reagent in order
to disassociate it, may remain associated with lipid when isolated and highly insoluble or forming
aggregate in neutral aqueous solution. It is assumed that only integral proteins important for
membrane structural integrity. Integral protein properties are (1). Grossly heterogeneous. (2).
Various protein of intact membrane show -helical conformation suggests that integral protein is
globular rather than spread out in layer and it did not attach to outer surface of lipid bilayer
(regarding membrane thickness) but intercalated within membrane.
Figure 2. Membrane protein
Major portion of phospholipids is in bilayer are based on the evident that membrane
undergo phase transition in temperature range similar to that of aqueous dispersion of
phospholipid extracted form membranes, besides x-ray diffraction and evident from other
experiment. Based on Benson model, protein and lipid form a single phase lipoprotein subunit
that is repeated indefinitely on two dimensions to constitute the membrane, this model suggest the
different lipid properties compare to that of bilayer model. Evidence at that time state that there is
no sufficient or sensitive quantitative that proof phospholipid are 100% in bilayers. So 30% of
phospholipid fraction might have different form from the rest of the lipid.
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Protein and lipid interaction play a role in various membrane function. Membrane
bound enzyme and antigen need lipids or specific phospholipids for its expression, bacterial
membrane are affected by the function of phospholipid on membrane bound proteins. The result
of calorimetric measurement showed that association of protein and phospholipids in membranes
did not affect phase transition. This indicates that there is no strong interaction between protein
and phospholipid, and they act independently, even though small fraction of lipid is more tightly
coupled to protein (integral protein).
c. Fluid Mosaic Model
Amphipathic structures adopted by integral protein (just like phospholipids) are under
thermodynamic control, they determined by AA sequence and covalent structure of protein and
by its interaction to molecular environment. Integral protein needs to have contact region with
water on both side of membrane. Some protein is membrane bound while some other is freely
soluble is because of the AA sequences that allow protein to use amphipathic structures or
distribution of ionic group spherically symmetrical. If the surface is spherically symmetrical it
will causes the protein to interact strongly with water. Mosaic structures can be diverse in several
ways, and resulted in specific binding of peripherals or the association of two or more integral
protein subunit. Thickness of mosaic membrane considered to be varied along the surface from
that across bilayer and that across protein region.
Hypothesis of substance that constitute of mosaic matrix: Functional cell membrane has
long range mosaic structures with the lipids constituting the matrix. The consequence are: if
the matrix is made of membrane protein, protein might be distributed in highly ordered two
dimensional array on the surface, but if the matrix is in lipid form, there will be no long range
interaction intrinsic to distribution of protein molecules, forming aperiodic random arrangement.
Long range order might present in certain cases. Besides it, lipids of functional cell membranes
are in fluid rather than a crystalline state. The fluid lipid matrix will cause the membrane to be
two dimensional liquid-like solution of aggregated integral protein dissolved in lipid bilayer. Still
the amphipathic structures will cause integral protein to maintain molecular orientation while
undergoing translational diffusion. Mosaic membrane with protein matrix should make rigid
structures with no translational diffusion of protein within membrane. Mosaic structure is
dynamic rather than static.
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Figure 3. The Original fluid mosaic model for membrane
Figure 4. Factors that affect membrane fluidity
d. Recent experimental Evidence
1
st
QUESTION: What is the evidence that protein embedded in membranes?
Method use : freeze etching method, to proof that integral protein (globular molecules) is
present, with its significant volume fraction, embedded to membrane.
Freeze etching : frozen specimen break using microtome. The frozen surface cut is shadow
casted with metal; the resulted surface replica produced then could be examined to reveal the
topography of cleaved surface. Freeze-fracture splits a membrane along the middle of the
bilayer. The surface is caused by cleavage of the membrane along with its interior hydrophobic
face (interior).
Figure 5. Freeze etching method
Result : Strongly suggest that massive numbers of protein are embedded in much
functional membranes. Mosaic like structures, consist of smooth matrix, is interrupted by large
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number of particles. These particles are found in huge uniformity. When the membrane layers are
viewed in the electron microscope, the interior of the bilayer appears cobblestoned, with protein
particles interspersed in a smooth matrix, in agreement with the uid mosaic model.
2
nd
QUESTION: How is the size and structure of integral protein?
Method : Using erythrocyte membrane
1. Proteolysis in normal compare to averted membrane and
2. Labeling membrane protein
Result : Certain integral protein have appropriate size and structure that can explain the
universality of membrane thickness (membranes are exposed from two sides).
3
rd
QUESTION: Distribution of component in the plain of membrane.
Prediction : There present essential random distribution of two dimensional in long range of
any integral protein membrane.
Method :
1. Electron microscopy, to visualize specific distribution of membrane antigen over large
area surface membrane.
2. Analyzing the distribution of Rho(D) antigen of human erythrocyte membrane cell, and
H-2 histocompatible alloantigen of mice erythrocyte membrane.
Result :
1. In human Rho(D) antigen :
The O Rh positive react with saturating amount
125
I labeled purified human antibody against
Rho(D)/anti Rho(D). The cell is lysed at air-water interface causing the cell membrane flattened.
The cell then picked up on electron microscope grid. Staining method is then occupied using
indirect stain (ferritin conjugated goat specific for human globulins). The results show that
whenever anti Rho(D)/ bound to Rho antigen on surface membrane, the ferritin goat attached. (
globulin human antibody became antigen for goat antibody). This indicates that there are
relations between clusters of 2-8 ferritin molecules on radius 300 . The cluster/unit area is in
balance between the total of
125
I labeled human and an Rho(D) molecules bound/unit area. Or in
other word every cluster ferritin bound to anti Rho(D) is equal to the cluster is the total of goat
antibody molecules bound to a single human Y globulin molecules (one cluster), then we can
conclude that Rho(D)/ antigen which possess integral protein properties are distributed randomly
in two dimensional array
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2. In mice
H-2 alloantigen site, showed that the cluster of ferritin on indirect stain are not associated like
the Rho(D) but occurs in patches. The patches contain various numbers of clusters and
composed of two dimensional array surface membranes and showed that long range
distribution of Rho(D) and H-2 antigen are present on surface membranes. Inner particles is
examined using freeze etching method resulted on random two dimensional arrangement.
Conclusion : Fluid mosaic model: integral protein random arrangement in two dimensional
arrays.
4
th
Question: Does protein consist of fluid state in intact internal membrane?
Method: Using receptor disk membrane retina of frog, the membrane is used because of its
unusual protein properties, Rhodopsin. Negative staining of dry surface membrane examination is
used and electron microscopic analyses are occupied.
Result: There present tightly packages ordered array particles (the particles is rhodopsin). Earlier
studies showed that there was a long range order of these particles distribution. But recent X-ray
diffraction data of wet pellet receptor disk membrane showed that (1) only a few order of
reflection was observed related to the spacing of Rhodopsin in membranes. It means, no
crystalline aperiodic arrangement of particles is present in membranes. (2) X-ray diffraction
maxima were consistent with idea that particles are in planar liquid-like state in intact
membranes. (3) Foreign protein absorption (Bovine serum albumin) to the membrane, alter x-ray
spacing of rhodopsin because albumin weakly bind to membrane to rhodopsin non-rigid
structures causing aggregates in membrane, indicating the liquid-like state.
Other studies:
1. Studies by Frye and Edidin: The determination of human and mouse antigenic component
of fused cell membranes using immunofluorescence method. Shortly after cell fusion, the
mouse and human antigenic components are segregated on different halves of fused cell
membrane, but after 40 min. the components were completely intermixed. Even the
additions of inhibitors of protein synthesis, ATP formation, and glutamine-dependent
synthetic pathways have no effect on intermixing. So they suggest that the intermixing is
because of diffusion of membrane, not because of removal and reinsertion of new copies
of membrane component into heterokaryon membrane. The study of Frye and Edidin can
be rationalized by fluid mosaic cell membrane structures as the intermixing of lipid-
protein and free diffusion occur.
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Figure 6. Cell fusion and intermixed state
Besides that there present several experiments showing that lipid membrane cannot diffuse
independently. Here are the following explanations of the experiments:
2. Studies form Wilson and Fox: lipids membranes are not readily interchangeable and not
free to diffuse independently. They use the -galactoside and -glucoside transport
system on mutant Escherichia coli that cannot synthesize unsaturated fatty acid, which
can be used to make phospholipid. Small fraction of protein might not be exchanged
rapidly with the bigger part of lipid. Their experiment suggests us that the membrane
phospholipid may not be the static one but only the small fraction of some of the
membrane lipid is structurally differentiated from the rest by strong binding to integral
protein.
3. Experiment by Mindich: more generally lipid and protein incorporation into bacterial
membranes can occur independently and as might expected from fluid mosaic structures,
there are a quite wide variation in ration of lipid-protein.
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th
Question: How does the asymmetry of membrane?
Method: Conjugation if several plant proteins to visualize the distribution of oligosaccharide on
membrane using electron microscope.
Evidence: Two surfaces of membranes are not identical in structure composition or function. This
asymmetry is come from the distribution of oligosaccharide on the two surface of membrane.
Cell-cell interaction and membrane biogenesis
The absence of oligosaccharide on inner membrane surface indicates that rotational
transition of glycoprotein of plasma membrane from the outer to the inner surface must occur in
slow rate. This conclusion probably applies to membrane protein other than glycoprotein. The
very slow transition can be explained by mosaic model and thermodynamic arguments. If integral
protein (including glycoprotein) in intact membrane, a large free energy (like phospholipid and
amphipathic structures) of activation is needed to rotate the ionic and polar region of the protein
through hydrophobic interior of the membrane to the other side.
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Relation of fluid mosaic model to this asymmetry is described as, while two-dimensional
translational diffusion of integral protein and membrane phospholipid occur freely, the rotational
diffusion of these components restricted in static way to the plane of membrane in which there
are no molecular tumbling occur at significant rate.
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th
Question: The problems of cell to cells interruption and membrane biogenesis
Method: Use the glycoprotein of erythrocyte.
Result: Absence of oligosaccharide in inner side membrane is caused by nearly neglected/non-
significant occurrence or slow rate of rotational transition of plasma membrane from outer to
inner membrane. This also applies for individual molecules of spin-labeled zwitterionic and ionic
phospholipid. The slow rate is in line with mosaic model and thermodynamic argument.
Mobilization of particles is applied only to components that exposed to outer surface.
e. The Fluid mosaic model and Membrane function
There have been explained before that membrane is two dimensional, viscous,
composed of amphipathic protein, and consist of lipid in thermodynamic equilibrium, but the
speculation of such diverse character should be discussed in respect to various mechanism of how
specific membrane cell functioned. New factors are introduced in this article are:
1. Physical or chemical disturbance of membrane may effect or alter particular
membrane component or set component.
2. Such things may cause redistribution of membrane components through translational
diffusion of viscous two dimensional membranes.
3. It allows new thermodynamic interaction to occur among altered components, and
this general mechanism may cause membrane-mediated phenomena such as nerve
impulse transmission.
Such condition in which the concept of alteration membrane structure-function phenomena are
illustrate in the article using malignant transformation of cell and the exposure of cryptic site.
Besides that the cooperative phenomena in membrane is also discussed by Singer and Nicholson.
They state that the effect of changes initiate in one site could be transmitted to another remote site
by coupling between the sites, causing number of important phenomena in membrane cell
Figure 7. Update model of fluid mosaic model
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Because models are hypotheses, replacing one model of membrane structure with another
does not imply that the original model was worthless. The acceptance or rejection of a model
depends on how well it ts observations and explains experimental results. New ndings may
make a model obsolete; even then, it may not be totally scrapped, but revised to incorporate the
new observations. The uid mosaic model is continually being rened. For example, groups of
proteins are often found associated in long-lasting, specialized patches, where they carry out
common functions. The lipids themselves appear to form dened regions as well. Also, the
membrane may be much more packed with proteins than imagined in the classic uid mosaic
modelcompare the updated model in Figure 7 with the original model in Figure 1 (Reece.2010.
p: 125).
CONSLUSION
1. The model of organization and structure of protein and lipid of biological membrane
is consistent with the thermodynamic restriction
2. The Important protein bound membranes are peripheral and integral protein.
Peripheral protein, protein that bound weakly by non-covalent interaction and
associate weakly with lipid while integral protein are the most abundant and
important for membrane structural integrity. Protein and lipid form a single phase
lipoprotein subunit that is repeated indefinitely on two dimensions to constitute the
membrane which are the bilayer characters of membrane lipid.
3. Protein that are integral to the membranes are a heterogeneous set of globular
molecules each arranged in amphipathic structures (ionic and highly polar group
protruding from the membranes into the aqueous phase, and the nonpolar groups
largely buried in the hydrophobic interior of the membranes). The globular
molecules are partially embedded in a matrix of phospholipid. The bulk of the
phospholipids are organized as a discontinuous fluid bilayer. So the fluid mosaic
structures are analogous to a two-dimensional oriented solution of integral protein
(lipoprotein) and viscous phospholipid bilayer.
4. Recent experiment with various technique and different membrane systems, are
consistent and add much detail to fluid mosaic model.
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REFERENCES
http://www.sumanasinc.com/webcontent/animations/content/immunohistochemistry.html
Brown, Bernard S. 1996. Biological Membranes. School of Biological Sciences University of
Manchester: UK
Krogh, David. 2011. Biology: A Guide to The Natural World, Fifth Edition. Pearson Benjamin
Cumming: USA
Reece, Jane. B., et- all. 2010. Campbell Biology, 9
th
Edition, Benjamin Cumming Publishing
Company Inc.: USA (Accessed form http://www.pearsonhighered.com/campbell9einfo/
assets/pdf/ Campbell9e_Ch07.pdf in august 2013)
Singer, S.J and Garth L. Nicholson. 1972. The Fluid Mosaic Model of the Structure of Cell
Membranes. Published by: American Association for the Advancement of Science. Vol.
175 pp. 720-731(Accessed form http://ressources.unisciel.fr/biocell/chap1/res/fluid%20
mosaic%20model %20of%2 0cell%20membranes%201972-Singer.pdf. in august 2013)