THE STRUCTURE OF CELL MEMBRANE S.J. Singer and Garth L. Nicolson C O M P I L E D By : RAJA NOVI ARISKA 8136173013 PENDIDIKAN BIOLOGI PASCA SARJANA UNIVERSITAS NEGERI MEDAN 2013/2014 Cell Biology Resume THE FLUID MOSAIC MODEL OF THE STRUCTURE OF CELL MEMBRANE S.J. Singer and Garth L. Nicolson C O M P I L E D By : RAJA NOVI ARISKA 8136173013 PENDIDIKAN BIOLOGI PASCA SARJANA UNIVERSITAS NEGERI MEDAN 2013/2014 Cell Biology Resume THE FLUID MOSAIC MODEL OF THE STRUCTURE OF CELL MEMBRANE S.J. Singer and Garth L. Nicolson C O M P I L E D By : RAJA NOVI ARISKA 8136173013 PENDIDIKAN BIOLOGI PASCA SARJANA UNIVERSITAS NEGERI MEDAN 2013/2014 I. Title : THE FLUID MOSAIC MODEL OF THE STRUCTURE OF CELL MEMBRANE II. Objectives : 1. Review some thermodynamics of macromolecular, particularly membrane system, in aqueous environment. 2. Discuss some properties of protein and lipid on functional membrane. 3. Describe the fluid mosaic model in detail. 4. Analyze some recent and more direct experimental evidence for proposed model. 5. Show that the fluid mosaic model suggest new ways of thinking about membranes function and membrane phenomena. III. Introduction The article of Singer and Nicolson is talked about the fluid mosaic model of cell membrane structure. Since the cell membranes play an important role in cell, the molecular of its structure need to be understand. Singer examined in considerable detail several models of the gross structural organization of membranes, in terms of the thermodynamics of macromolecular systems and in the light of the then available experimental evidence. From his analysis, it was concluded that a mosaic structure of alternating globular proteins and phospholipid-bilayer was the only membrane model among those analyzed that was simultaneously consistent with thermodynamic restrictions and with all the experimental data available. This article present and discuss a fluid mosaic model of membrane structure, its components properties, and propose that it is applicable to most biological membranes, such as plasmalemmal and intracellular membranes, including the membranes of different cell organelles, such as mitochondria and chloroplasts. These membranes are henceforth referred to as functional membranes. IV. Discussion a. Thermodynamics and Membrane Structure The fluid mosaic model has evolved by a series of stages from earlier version. It indicates that the membrane systems composed of two kinds of non- covalent interactions are most important, hydrophobic and hydrophilic, known as amphipathic. Hydrophobic as tail (water-fearing) interactions means a set of thermodynamic factors that are responsible for the sequestering of hydrophobic or non-polar groups away from water, as, for example, the immiscibility of hydrocarbons and water. To be specific, it requires the expenditure of 2.6 kilocalories of free energy to transfer a mole of methane from a non-polar medium to water at 25C. Hydrophilic as head (water-loving) interactions is meant a set of thermodynamic factors that are responsible for the preference of ionic and polar groups for an aqueous rather than a non-polar environment. Thus, the free energy required to transfer a mole of zwitterionic glycine from water to acetone is about 6.0 kcal at 25C, showing that ion pairs strongly prefer to be in water than in a non-polar medium. The hydrophilic are face outward and likely to encounter a wateryenvironment. The hydrophobic are face inward, where there is no water. When phospholipids are placed in water, they naturally form a spherical bilayer because of the chemical properties of the heads and the tails (Mader.2004). Figure 1. phospholipid molecule (source: Freeman, 2003) IV. Discussion a. Thermodynamics and Membrane Structure The fluid mosaic model has evolved by a series of stages from earlier version. It indicates that the membrane systems composed of two kinds of non- covalent interactions are most important, hydrophobic and hydrophilic, known as amphipathic. Hydrophobic as tail (water-fearing) interactions means a set of thermodynamic factors that are responsible for the sequestering of hydrophobic or non-polar groups away from water, as, for example, the immiscibility of hydrocarbons and water. To be specific, it requires the expenditure of 2.6 kilocalories of free energy to transfer a mole of methane from a non-polar medium to water at 25C. Hydrophilic as head (water-loving) interactions is meant a set of thermodynamic factors that are responsible for the preference of ionic and polar groups for an aqueous rather than a non-polar environment. Thus, the free energy required to transfer a mole of zwitterionic glycine from water to acetone is about 6.0 kcal at 25C, showing that ion pairs strongly prefer to be in water than in a non-polar medium. The hydrophilic are face outward and likely to encounter a wateryenvironment. The hydrophobic are face inward, where there is no water. When phospholipids are placed in water, they naturally form a spherical bilayer because of the chemical properties of the heads and the tails (Mader.2004). Figure 1. phospholipid molecule (source: Freeman, 2003) IV. Discussion a. Thermodynamics and Membrane Structure The fluid mosaic model has evolved by a series of stages from earlier version. It indicates that the membrane systems composed of two kinds of non- covalent interactions are most important, hydrophobic and hydrophilic, known as amphipathic. Hydrophobic as tail (water-fearing) interactions means a set of thermodynamic factors that are responsible for the sequestering of hydrophobic or non-polar groups away from water, as, for example, the immiscibility of hydrocarbons and water. To be specific, it requires the expenditure of 2.6 kilocalories of free energy to transfer a mole of methane from a non-polar medium to water at 25C. Hydrophilic as head (water-loving) interactions is meant a set of thermodynamic factors that are responsible for the preference of ionic and polar groups for an aqueous rather than a non-polar environment. Thus, the free energy required to transfer a mole of zwitterionic glycine from water to acetone is about 6.0 kcal at 25C, showing that ion pairs strongly prefer to be in water than in a non-polar medium. The hydrophilic are face outward and likely to encounter a wateryenvironment. The hydrophobic are face inward, where there is no water. When phospholipids are placed in water, they naturally form a spherical bilayer because of the chemical properties of the heads and the tails (Mader.2004). Figure 1. phospholipid molecule (source: Freeman, 2003) There are other non-covalent interactions, such as hydrogen bonding and electrostatic interactions, which also contribute to determine macromolecular structure. However, with respect to gross structure, with which we are now concerned, these are very likely of secondary magnitude compared to hydrophobic and hydrophilic interactions. The non-polar fatty acid chains of the phospholipids are sequestered together away from contact with water, thereby maximizing hydrophobic interactions. Furthermore, the ionic and zwitter-ionic groups are in direct contact with the aqueous phase at the exterior surfaces of the bilayer, thereby maximizing hydrophilic interactions. In the case of zwitterionic phospholipids such as phosphatidylcholine, dipole-dipole interactions between ion pairs at the surface of the bilayer may also contribute to the stabilization of the, bilayer structure. The tail in cell membrane have variable in length. It caused by the cis- double bound in one tail. It cause small kink in the structure of cell membrane and affect the packing and fluidity of cell membrane. (Alberts, 2008) Figure 2. Molecular structure of amphipathic structure The double cis-bond makes more difficult to pack the chains together, thus making lipid bilayer hard to freeze. In addition, because of the hydrocarbon chains of unsaturated lipid is more spread apart, it has thinner structure than the saturated lipid . There are other non-covalent interactions, such as hydrogen bonding and electrostatic interactions, which also contribute to determine macromolecular structure. However, with respect to gross structure, with which we are now concerned, these are very likely of secondary magnitude compared to hydrophobic and hydrophilic interactions. The non-polar fatty acid chains of the phospholipids are sequestered together away from contact with water, thereby maximizing hydrophobic interactions. Furthermore, the ionic and zwitter-ionic groups are in direct contact with the aqueous phase at the exterior surfaces of the bilayer, thereby maximizing hydrophilic interactions. In the case of zwitterionic phospholipids such as phosphatidylcholine, dipole-dipole interactions between ion pairs at the surface of the bilayer may also contribute to the stabilization of the, bilayer structure. The tail in cell membrane have variable in length. It caused by the cis- double bound in one tail. It cause small kink in the structure of cell membrane and affect the packing and fluidity of cell membrane. (Alberts, 2008) Figure 2. Molecular structure of amphipathic structure The double cis-bond makes more difficult to pack the chains together, thus making lipid bilayer hard to freeze. In addition, because of the hydrocarbon chains of unsaturated lipid is more spread apart, it has thinner structure than the saturated lipid . There are other non-covalent interactions, such as hydrogen bonding and electrostatic interactions, which also contribute to determine macromolecular structure. However, with respect to gross structure, with which we are now concerned, these are very likely of secondary magnitude compared to hydrophobic and hydrophilic interactions. The non-polar fatty acid chains of the phospholipids are sequestered together away from contact with water, thereby maximizing hydrophobic interactions. Furthermore, the ionic and zwitter-ionic groups are in direct contact with the aqueous phase at the exterior surfaces of the bilayer, thereby maximizing hydrophilic interactions. In the case of zwitterionic phospholipids such as phosphatidylcholine, dipole-dipole interactions between ion pairs at the surface of the bilayer may also contribute to the stabilization of the, bilayer structure. The tail in cell membrane have variable in length. It caused by the cis- double bound in one tail. It cause small kink in the structure of cell membrane and affect the packing and fluidity of cell membrane. (Alberts, 2008) Figure 2. Molecular structure of amphipathic structure The double cis-bond makes more difficult to pack the chains together, thus making lipid bilayer hard to freeze. In addition, because of the hydrocarbon chains of unsaturated lipid is more spread apart, it has thinner structure than the saturated lipid . b. Some Properties of Membrane Components Peripheral and integral proteins. Peripheral protein has several characteristics: (i) They require only mild treatments, such as an increase in the ionic strength of the medium or the addition of a chelating agent, to dissociate them molecularly intact from the membrane; (ii) They dissociate free of lipids; and (iii) In the dissociated state they are relatively soluble in neutral aqueous buffers is held to the membrane only by rather weak non-covalent (perhaps mainly electrostatic) interactions and is not strongly associated with membrane lipid. Figure 3. Protein of lipid bilayer On the other hand, the integral proteins also have several characteristics, namely: (i) They require much more drastic treatments, with reagents such as detergents, bile acids, protein denaturants, or organic solvents, to dissociate them from membranes; (ii) In many instances, they remain associated with lipids when isolated; (iii) If completely freed of lipids, they are usually highly insoluble or aggregated in neutral aqueous buffers. b. Some Properties of Membrane Components Peripheral and integral proteins. Peripheral protein has several characteristics: (i) They require only mild treatments, such as an increase in the ionic strength of the medium or the addition of a chelating agent, to dissociate them molecularly intact from the membrane; (ii) They dissociate free of lipids; and (iii) In the dissociated state they are relatively soluble in neutral aqueous buffers is held to the membrane only by rather weak non-covalent (perhaps mainly electrostatic) interactions and is not strongly associated with membrane lipid. Figure 3. Protein of lipid bilayer On the other hand, the integral proteins also have several characteristics, namely: (i) They require much more drastic treatments, with reagents such as detergents, bile acids, protein denaturants, or organic solvents, to dissociate them from membranes; (ii) In many instances, they remain associated with lipids when isolated; (iii) If completely freed of lipids, they are usually highly insoluble or aggregated in neutral aqueous buffers. b. Some Properties of Membrane Components Peripheral and integral proteins. Peripheral protein has several characteristics: (i) They require only mild treatments, such as an increase in the ionic strength of the medium or the addition of a chelating agent, to dissociate them molecularly intact from the membrane; (ii) They dissociate free of lipids; and (iii) In the dissociated state they are relatively soluble in neutral aqueous buffers is held to the membrane only by rather weak non-covalent (perhaps mainly electrostatic) interactions and is not strongly associated with membrane lipid. Figure 3. Protein of lipid bilayer On the other hand, the integral proteins also have several characteristics, namely: (i) They require much more drastic treatments, with reagents such as detergents, bile acids, protein denaturants, or organic solvents, to dissociate them from membranes; (ii) In many instances, they remain associated with lipids when isolated; (iii) If completely freed of lipids, they are usually highly insoluble or aggregated in neutral aqueous buffers. Figure 4. Type of protein based on its location Integral proteins grossly heterogeneous and vary in molecular weight. It also suggested that the integral proteins are largely globular in shape rather than spread in a monolayer. Lipid-anchored membrane proteins are bound covalently to one or more lipid molecules. The hydrophobic carbon chain of the attached lipid is embedded in one leaflet of the membrane and anchors the protein to the membrane. The polypeptide chain itself does not enter the phospholipid bilayer. Figure 3. properties of protein in cell membrane Figure 4. Type of protein based on its location Integral proteins grossly heterogeneous and vary in molecular weight. It also suggested that the integral proteins are largely globular in shape rather than spread in a monolayer. Lipid-anchored membrane proteins are bound covalently to one or more lipid molecules. The hydrophobic carbon chain of the attached lipid is embedded in one leaflet of the membrane and anchors the protein to the membrane. The polypeptide chain itself does not enter the phospholipid bilayer. Figure 3. properties of protein in cell membrane Figure 4. Type of protein based on its location Integral proteins grossly heterogeneous and vary in molecular weight. It also suggested that the integral proteins are largely globular in shape rather than spread in a monolayer. Lipid-anchored membrane proteins are bound covalently to one or more lipid molecules. The hydrophobic carbon chain of the attached lipid is embedded in one leaflet of the membrane and anchors the protein to the membrane. The polypeptide chain itself does not enter the phospholipid bilayer. Figure 3. properties of protein in cell membrane c. Fluid Mosaic Model The characteristic of globular protein is same as the lipid bilayer, namely amphipathic. They are structurally asymmetry, with one high polar end and one non polar end. The highly polar region is one in which the ionic amino acid residues and any covalently bound saccharide residues are clustered, and which is in contact with the aqueous phase in the intact membrane; the nonpolar region is devoid of ionic and saccharide residues, contains many of the nonpolar residues, and is embedded in the hydrophobic interior of the membrane. If the protein have the appropriate amino sequences and contain amphiphatic structure, it can be included as integral protein. An integral protein molecule with the appropriate size and structure, or a suitable aggregate of integral proteins (below) may transverse the entire membrane that is, they have regions in contact with the aqueous solvent on both sides of the membrane. The reason why some proteins are membrane bound and others are freely soluble in the cytoplasm because the amino acid sequence of the particular protein allows it to adopt an amphipathic structure or, on the contrary, to adopt a structure in which the distribution of ionic groups is nearly spherically symmetrical, in the lowest free energy state of the system. If the ionic distribution on the protein surface were symmetrical, the protein would be capable of interacting strongly with water all over its exterior surface, that is, it would be a monodisperse soluble protein. At body temperature, the phospholipid bilayer is a liquid; it has the consistency of olive oil, and the proteins are able to change their positions by moving laterally. The fluid-mosaic model, a working description of membrane structure, suggests that the protein molecules have a changing pattern (form a mosaic) within the fluid phospholipid bilayer. Our plasma membranes also contain a substantial number of cholesterol molecules. These molecules lend stability to the phospholipid bilayer and prevent a drastic decrease in fluidity at low temperatures. Figure 5. phospholipid bilayer structure Short chains of sugars are attached to the outer surfaces of some protein and lipid molecules (called glycoproteins and glycolipids, respectively). These carbohydrate chains, specific to each cell, mark the cell as belonging to a particular individual and account for such characteristics as blood type or why a patients system sometimes rejects an organ transplant. Some glycoproteins have a special configuration that allows them to act as a receptor for a chemical messenger such as a hormone. Some plasma membrane proteins form channels through which certain substances can enter cells, while others are carriers involved in the passage of molecules through the membrane (Fremann.2003) Figure 5. phospholipid bilayer structure Short chains of sugars are attached to the outer surfaces of some protein and lipid molecules (called glycoproteins and glycolipids, respectively). These carbohydrate chains, specific to each cell, mark the cell as belonging to a particular individual and account for such characteristics as blood type or why a patients system sometimes rejects an organ transplant. Some glycoproteins have a special configuration that allows them to act as a receptor for a chemical messenger such as a hormone. Some plasma membrane proteins form channels through which certain substances can enter cells, while others are carriers involved in the passage of molecules through the membrane (Fremann.2003) Figure 5. phospholipid bilayer structure Short chains of sugars are attached to the outer surfaces of some protein and lipid molecules (called glycoproteins and glycolipids, respectively). These carbohydrate chains, specific to each cell, mark the cell as belonging to a particular individual and account for such characteristics as blood type or why a patients system sometimes rejects an organ transplant. Some glycoproteins have a special configuration that allows them to act as a receptor for a chemical messenger such as a hormone. Some plasma membrane proteins form channels through which certain substances can enter cells, while others are carriers involved in the passage of molecules through the membrane (Fremann.2003) Figure 6. Dynamic of Phospholipid Matrix of the mosaic, lipid or protein? It is not well determine which components are arrange the matrix of the mosaic. This question must be answered when the third dimension of the mosaic structure is specified. If the membrane proteins formed the matrix of the mosaic, defined by specific contacts between the molecules of different integral proteins, protein A might be distributed in a highly ordered, two dimensional array on the surface. On the other hand, if lipid formed the matrix of the mosaic, there would be no long- range interactions intrinsic to the membrane influencing the distribution of A molecules, and they should there-fore be distributed in an aperiodic random arrangement on the membrane surface. If a membrane consisted of integral proteins dispersed in a fluid lipid matrix, the membrane would in effect be a two-dimensional liquid-like solution of mon-omeric or aggregated integral proteins (or lipoproteins) dissolved in the lipid bilayer. The mosaic structure would be a dynamic rather than a static one. The integral proteins would be expected to undergo translational diffusion within the membrane, at rates determined in part by the effective viscosity of the lipid, unless they were tied down by some specific interactions intrinsic or extrinsic to the membrane. However, because of their amphipathic structures, the integral proteins would maintain their molecular orientation and their degree of intercalation in the membrane while undergoing translational diffusion in the plane of the membrane. In contrast, if the matrix of the mosaic were constituted of integral proteins, the long-range structure of the membrane would be essentially static. Large energies of activation would be required for a protein component to diffuse in the plane of the membrane from one region to a distant one because of the many non-covalent bonds between the proteins that would have to be simultaneously broken for exchange to take place. Therefore, a mosaic membrane with a protein matrix should make for a relatively rigid structure with essentially no translational diffusion of its protein components within the membrane. d. Some evidence related to mosaic model 1. Evidence for proteins embedded in membranes The results of recent freeze-etching experiments with membranes strongly suggest that a substantial amount of protein is deeply embedded in many functional membranes. Methods a frozen specimen is fractured with a microtome knife; some of the frozen water is sub-limed (etched) from the fractured surface if desired; the surface is then shadow cast with metal, and the surface replica is examined in the electron microscope. A characteristic feature of the exposed surface of most functional membranes examined by this technique, including plasmalemmal, vacuolar, nu-clear, chloroplast, mitochondrial, and bacterial membranes is a mosaic-like structure consisting of a smooth matrix interrupted by a large number of particles. These particles have a fairly characteristic uniform size for a particular membrane, for example, about 85 diameter for erythrocyte membranes. Such surfaces result from the cleavage of a membrane along its interior hydrophobic face. 2. Distribution of component in the plain of membrane. The distribution of component in plain of membrane can be visualized by using electron microscopy. It is shown the distribution of membrane antigen over large area surface membrane. Thus, analyzing the distribution of Rho(D) antigen of human erythrocyte membrane cell. 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 relation between clusters of 2-8 ferritin molecules on radius 300 A. The cluster/unit area is in balance between the total oI 125 I labeled human and an Rho(D) molecules bound/unit area. Or in other word every cluster ferritin bound to anti Rho(D) and the cluster is the total of goat antibody molecules bound to a single human Y globulin molecules (one cluster),a we can conclude that Rho(D)/ antigen which possess integral protein properties are distributed randomly in two dimensional array. 3. Protein is consist fluid state in intact internal membrane There present tightly packages ordered array particles (the particles in 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 (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 relation between clusters of 2-8 ferritin molecules on radius 300 A. The cluster/unit area is in balance between the total oI 125 I labeled human and an Rho(D) molecules bound/unit area. Or in other word every cluster ferritin bound to anti Rho(D) and the cluster is the total of goat antibody molecules bound to a single human Y globulin molecules (one cluster),a we can conclude that Rho(D)/ antigen which possess integral protein properties are distributed randomly in two dimensional array. 3. Protein is consist fluid state in intact internal membrane There present tightly packages ordered array particles (the particles in 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 (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 relation between clusters of 2-8 ferritin molecules on radius 300 A. The cluster/unit area is in balance between the total oI 125 I labeled human and an Rho(D) molecules bound/unit area. Or in other word every cluster ferritin bound to anti Rho(D) and the cluster is the total of goat antibody molecules bound to a single human Y globulin molecules (one cluster),a we can conclude that Rho(D)/ antigen which possess integral protein properties are distributed randomly in two dimensional array. 3. Protein is consist fluid state in intact internal membrane There present tightly packages ordered array particles (the particles in 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. 4. The asymmetry of membrane 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. Technique : There exist plant proteins, called lectins or plant agglutinins, which bind to specific sugar residues, and, as a result, can cause the agglutination of cells bearing the sugar residues on their surfaces. The authors have been able to visualize the distribution of oligosaccharides on membranes in the electron microscope. e. The Fluid Mosaic Model and membrane functions The structure of cell membrane which viscous with amphipathic solution and lipid instantaneous thermodynamic equilibrium is lead to several functions related to transportation within and to the cell. Physical and chemical perturbation can affect and change the components of cell membrane, thus provide new thermodynamic interaction of altered components. 1. Malignant transformation of cells and the "exposure of cryptic sites. Malignant trans-formation is closely correlated with a greatly increased capacity for the trans-formed cells to be agglutinated by several saccharides binding plant agglutinins. Mild treatment of normal cells with proteolytic enzymes can render malignant also more readily agglutinable by these protein agglutinins. Burger has suggested, therefore, that the agglutinin-binding sites are pres-ent on the membrane surfaces of nor-mal cells but are "cryptic" and that proteolytic digestion of normal cells or the processes of malignant transformation "exposes" these cryptic sites on the membrane surface. In some cases, quantitative binding studies have indeed indicated that no significant change in the numbers of agglutinin-binding sites on the membrane accompanies either mild proteolysis of normal cells or malignant transformation. 2. Cooperative phenomena in membrane Trans effects refer to cooperative (allosteric) changes that have been postulated to operate at some localized region on the membrane surface, to transmit an effect from one side of the membrane to the other. For example, fan integral protein may exist in the membrane as an aggregate of two (or more) subunits, one of which is exposed to the aqueous solution at the outer surface of the membrane, and the other is exposed to the cytoplasm at the inner surface. The specific binding of a drug or hormone molecule to the active site of the outward- oriented subunit may induce a conformational rearrangement within the aggregate, and thereby change some functional property of the aggregate or of its inward-oriented subunit. By cis effects, on the other hand, we refer to cooperative changes that may be produced over the entire membrane, or at least large areas of it, as a consequence of some event or events occurring at only one or a few localized points on the membrane surface. For example, the killing effects of certain bacteriocins on bacteria, the lysis of the cortical granules of egg cells upon fertilization of eggs by sperm, and the interaction of growth hormone with erythrocyte membranes are cases which may involve transmission and amplification of local-ized events over the entire surface of a membrane. V. Conclusion 1. The structure of phospholipid bilayer in aqueous environment is in amphipathic structure, which means, the lipid bilayer consist of hydrophilic head and hydrophobic tails. The hydrophilic is consist of covalent bond (high polar) of phosphate and glycerol, while in hydropobic (non-polar) the tails is composed of fatty acid. Both of this structure is works cooperatively makes the structure for its proper function and its composition affect the fluidity of lipid bilayer. 2. In lipid bilayer, there are two major proteins arrange its structure, peripheral and integral. The peripheral is located on the side of the bilayer and easier to breaks by mild treatments, while the integral is embedded in the bilayer. The integral is assumed as the main protein in the formation of lipid bilayer. The lipid itself has a major role in the case of the fluidity of the cell membrane. Since the tail is consist of the fatty acid, the structure of tail effect the fluidity of bilayer, especially the unsaturated, kinky structure. 3. The structure of fluid-mosaic at body temperature is a liquid; a working description of membrane structure, suggests that the protein molecules have a changing pattern (form a mosaic) within the fluid phospholipid bilayer. Our plasma membranes also contain a substantial number of cholesterol molecules. These molecules lend stability to the phospholipid bilayer and prevent a drastic decrease in fluidity at low temperatures. 4. There are four some recent evidence of cell membrane structures. a. protein are embedded in membrane b. the distribution of component in membrane c. Protein is consist fluid state in intact internal membrane d. The asymmetry of membrane 5. The structure of cell membrane which viscous with amphipathic solution and lipid instantaneous thermodynamic equilibrium is lead to several function, related to transportation within and to the cell. Physical and chemical perturbation can affect and change the components of cell membrane, thus provide new thermodynamic interaction of altered components. REFERENCES Alberts, Bruce et al. 2008. Molecular Biology of the Cell, Fifth Edition. Garland Science, Taylor and Francis Group. USA Freeman.2003. Molecular Biology. (downloading from 4shared.com on January, 2013) Mader, Sylvia S. 2004. Understanding Human Anatomy and Physiology, Fifth Edition. Mc. Graw-Hill. USA 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. 175pp. 720-731.