The fluid mosaic model explains various characteristics regarding the structure of functional cell membranes. According to this biological model, there is a lipid bilayer (two molecules thick layer consisting primarily of amphipathic phospholipids) in which proteinmolecules are embedded. The phospholipid bilayer gives fluidity and elasticity to the membrane. Small amounts of carbohydrates are also found in the cell membrane. The biological model, which was devised by Seymour Jonathan Singer and Garth L. Nicolson in 1972,[1] describes the cell membrane as a two-dimensional liquid that restricts the lateral diffusion of membrane components. Such domains are defined by the existence of regions within the membrane with special lipid and protein cocoon that promote the formation of lipid rafts or protein and glycoprotein complexes. Another way to define membrane domains is the association of the lipid membrane with the cytoskeleton filaments and the extracellular matrix through membrane proteins.[2] The current model describes important features relevant to many cellular processes, including: cell-cell signaling, apoptosis, cell division, membrane budding, and cell fusion. The fluid mosaic model is the most acceptable model of the plasma membrane. In this definition of the cell membrane, its main function is to act as a barrier between the contents inside the cell and the extracellular environment.
It provides selective permeability to the cell membrane.
The hydrophilic phosphate side is outwards and hydrophobic inwards.
Carbohydrates
Attached to proteins on outside membrane layers
It helps in cell-to-cell recognition.
Cholesterol
Between phospholipids and phospholipid bilayers
It helps the plasma membrane to retain its fluidity.
Proteins
Embedded within or on the surface of phospholipid layers
These form channels to allow the movement of molecules.
Experimental evidence
The fluid property of functional biological membranes had been determined through labeling experiments, x-ray diffraction, and calorimetry. These studies showed that integral membrane proteins diffuse at rates affected by the viscosity of the lipid bilayer in which they were embedded, and demonstrated that the molecules within the cell membrane are dynamic rather than static.[1]
Previous models of biological membranes included the Robertson Unit Membrane Model and the Davson-Danielli Tri-Layer model.[2] These models had proteins present as sheets neighboring a lipid layer, rather than incorporated into the phospholipid bilayer. Other models described repeating, regular units of protein and lipid. These models were not well supported by microscopy and thermodynamic data, and did not accommodate evidence for dynamic membrane properties.[2]
The Frye-Edidin experiment showed that when two cells are fused the proteins of both diffuse around the membrane and mingle rather than being locked to their area of the membrane.
An important experiment that provided evidence supporting fluid and dynamic biological was performed by Frye and Edidin. They used Sendai virus to force human and mouse cells to fuse and form a heterokaryon. Using antibody staining, they were able to show that the mouse and human proteins remained segregated to separate halves of the heterokaryon a short time after cell fusion. However, the proteins eventually diffused and over time the border between the two halves was lost. Lowering the temperature slowed the rate of this diffusion by causing the membrane phospholipids to transition from a fluid to a gel phase.[3] Singer and Nicolson rationalized the results of these experiments using their fluid mosaic model.[1]
The fluid mosaic model explains changes in structure and behavior of cell membranes under different temperatures, as well as the association of membrane proteins with the membranes. While Singer and Nicolson had substantial evidence drawn from multiple subfields to support their model, recent advances in fluorescence microscopy and structural biology have validated the fluid mosaic nature of cell membranes.
Subsequent developments
Membrane asymmetry
Additionally, the two leaflets of biological membranes are asymmetric and divided into subdomains composed of specific proteins or lipids, allowing spatial segregation of biological processes associated with membranes. Cholesterol and cholesterol-interacting proteins can concentrate into lipid rafts and constrain cell signaling processes to only these rafts.[4] Another form of asymmetry was shown by the work of Mouritsen and Bloom in 1984, where they proposed a Mattress Model of lipid-protein interactions to address the biophysical evidence that the membrane can range in thickness and hydrophobicity of proteins.[5]
Non-bilayer membranes
The existence of non-bilayer lipid formations with important biological functions was confirmed subsequent to publication of the fluid mosaic model. These membrane structures may be useful when the cell needs to propagate a non bilayer form, which occurs during cell division and the formation of a gap junction.[6]
Membrane curvature
The membrane bilayer is not always flat. Local curvature of the membrane can be caused by the asymmetry and non-bilayer organization of lipids as discussed above. More dramatic and functional curvature is achieved through BAR domains, which bind to phosphatidylinositol on the membrane surface, assisting in vesicle formation, organelle formation and cell division.[7] Curvature development is in constant flux and contributes to the dynamic nature of biological membranes.[8]
Lipid movement within the membrane
During the 1970s, it was acknowledged that individual lipid molecules undergo free lateral diffusion within each of the layers of the lipid membrane.[9] Diffusion occurs at a high speed, with an average lipid molecule diffusing ~2µm, approximately the length of a large bacterial cell, in about 1 second.[9] It has also been observed that individual lipid molecules rotate rapidly around their own axis.[9] Moreover, phospholipid molecules can, although they seldom do, migrate from one side of the lipid bilayer to the other (a process known as flip-flop). However, flip-flop movement is enhanced by flippase enzymes.[10] The processes described above influence the disordered nature of lipid molecules and interacting proteins in the lipid membranes, with consequences to membrane fluidity, signaling, trafficking and function.
Restrictions to bilayer fluidity
There are restrictions to the lateral mobility of the lipid and protein components in the fluid membrane imposed by the formation of subdomains within the lipid bilayer. These subdomains arise by several processes e.g. binding of membrane components to the extracellular matrix, nanometric membrane regions with a particular biochemical composition that promote the formation of lipid rafts and protein complexes mediated by protein-protein interactions.[2] Furthermore, protein-cytoskeleton associations mediate the formation of “cytoskeletal fences”, corrals wherein lipid and membrane proteins can diffuse freely, but that they can seldom leave.[2] Restriction on lateral diffusion rates of membrane components is very important because it allows the functional specialization of particular regions within the cell membranes.
Lipid rafts
Lipid rafts are membrane nanometric platforms with a particular lipid and protein composition that laterally diffuse, navigating on the liquid bilipid layer. Sphingolipids and cholesterol are important building blocks of the lipid rafts.[11]
Protein complexes
Cell membrane proteins and glycoproteins do not exist as single elements of the lipid membrane, as first proposed by Singer and Nicolson in 1972. Rather, they occur as diffusing complexes within the membrane.[2] The assembly of single molecules into these macromolecular complexes has important functional consequences for the cell; such as ion and metabolite transport, signaling, cell adhesion, and migration.[2]
Cytoskeletal fences (corrals) and binding to the extracellular matrix
Some proteins embedded in the bilipid layer interact with the extracellular matrix outside the cell, cytoskeleton filaments inside the cell, and septin ring-like structures. These interactions have a strong influence on shape and structure, as well as on compartmentalization. Moreover, they impose physical constraints that restrict the free lateral diffusion of proteins and at least some lipids within the bilipid layer.[2]
When integral proteins of the lipid bilayer are tethered to the extracellular matrix, they are unable to diffuse freely. Proteins with a long intracellular domain may collide with a fence formed by cytoskeleton filaments.[12] Both processes restrict the diffusion of proteins and lipids directly involved, as well as of other interacting components of the cell membranes.
S.cerevisiae septins Septin ring-like structures (in green) can pinch cell membranes and split them into subdomains.
Septins are a family of GTP-binding proteins highly conserved among eukaryotes. Prokaryotes have similar proteins called paraseptins. They form compartmentalizing ring-like structures strongly associated with the cell membranes. Septins are involved in the formation of structures such as, cilia and flagella, dendritic spines, and yeast buds.[13]
Historical timeline
1895 – Ernest Overton hypothesized that cell membranes are made out of lipids.[14]
1925 – Evert Gorter and François Grendel found that red blood cell membranes are formed by a fatty layer two molecules thick, i.e. they described the bilipid nature of the cell membrane.[15]
1935 – Hugh Davson and James Danielli proposed that lipid membranes are layers composed by proteins and lipids with pore-like structures that allow specific permeability for certain molecules. Then, they suggested a model for the cell membrane, consisting of a lipid layer surrounded by protein layers at both sides of it.[16]
1957 – J. David Robertson, based on electron microscopy studies, establishes the "Unit Membrane Hypothesis". This, states that all membranes in the cell, i.e. plasma and organelle membranes, have the same structure: a bilayer of phospholipids with monolayers of proteins at both sides of it.[17]
1972 – SJ Singer and GL Nicolson proposed the fluid mosaic model as an explanation for the data and latest evidence regarding the structure and thermodynamics of cell membranes.[1]
↑ Frye LD, Edidin M (September 1970). "The rapid intermixing of cell surface antigens after formation of mouse-human heterokaryons". Journal of Cell Science. 7 (2): 319–335. doi:10.1242/jcs.7.2.319. PMID4098863.
↑ Silvius JR (December 2005). "Partitioning of membrane molecules between raft and non-raft domains: insights from model-membrane studies". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1746 (3): 193–202. doi:10.1016/j.bbamcr.2005.09.003. PMID16271405.
↑ Rodríguez-García R, Arriaga LR, Mell M, Moleiro LH, López-Montero I, Monroy F (March 2009). "Bimodal spectrum for the curvature fluctuations of bilayer vesicles: pure bending plus hybrid curvature-dilation modes". Physical Review Letters. 102 (12): 128101. doi:10.1103/PhysRevLett.102.128101. PMID19392326.
↑ Danielli J, Davson H (1935). "A contribution to the theory of permeability of thin films". Journal of Cellular and Comparative Physiology. 5 (4): 495–508. doi:10.1002/jcp.1030050409.
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the cell and another. Biological membranes, in the form of eukaryotic cell membranes, consist of a phospholipid bilayer with embedded, integral and peripheral proteins used in communication and transportation of chemicals and ions. The bulk of lipids in a cell membrane provides a fluid matrix for proteins to rotate and laterally diffuse for physiological functioning. Proteins are adapted to high membrane fluidity environment of the lipid bilayer with the presence of an annular lipid shell, consisting of lipid molecules bound tightly to the surface of integral membrane proteins. The cell membranes are different from the isolating tissues formed by layers of cells, such as mucous membranes, basement membranes, and serous membranes.
Facilitated diffusion is the process of spontaneous passive transport of molecules or ions across a biological membrane via specific transmembrane integral proteins. Being passive, facilitated transport does not directly require chemical energy from ATP hydrolysis in the transport step itself; rather, molecules and ions move down their concentration gradient according to the principles of diffusion.
Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue. Marine phospholipids typically have omega-3 fatty acids EPA and DHA integrated as part of the phospholipid molecule. The phosphate group can be modified with simple organic molecules such as choline, ethanolamine or serine.
The lipid bilayer is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many viruses are made of a lipid bilayer, as are the nuclear membrane surrounding the cell nucleus, and membranes of the membrane-bound organelles in the cell. The lipid bilayer is the barrier that keeps ions, proteins and other molecules where they are needed and prevents them from diffusing into areas where they should not be. Lipid bilayers are ideally suited to this role, even though they are only a few nanometers in width, because they are impermeable to most water-soluble (hydrophilic) molecules. Bilayers are particularly impermeable to ions, which allows cells to regulate salt concentrations and pH by transporting ions across their membranes using proteins called ion pumps.
Semipermeable membrane is a type of biological or synthetic, polymeric membrane that allows certain molecules or ions to pass through it by osmosis. The rate of passage depends on the pressure, concentration, and temperature of the molecules or solutes on either side, as well as the permeability of the membrane to each solute. Depending on the membrane and the solute, permeability may depend on solute size, solubility, properties, or chemistry. How the membrane is constructed to be selective in its permeability will determine the rate and the permeability. Many natural and synthetic materials which are rather thick are also semipermeable. One example of this is the thin film on the inside of an egg.
The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains controversial. Indeed, Kervin and Overduin imply that lipid rafts are misconstrued protein islands, which they propose form through a proteolipid code. Nonetheless, it has been proposed that they are specialized membrane microdomains which compartmentalize cellular processes by serving as organising centers for the assembly of signaling molecules, allowing a closer interaction of protein receptors and their effectors to promote kinetically favorable interactions necessary for the signal transduction. Lipid rafts influence membrane fluidity and membrane protein trafficking, thereby regulating neurotransmission and receptor trafficking. Lipid rafts are more ordered and tightly packed than the surrounding bilayer, but float freely within the membrane bilayer. Although more common in the cell membrane, lipid rafts have also been reported in other parts of the cell, such as the Golgi apparatus and lysosomes.
Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids. In humans, SPH represents ~85% of all sphingolipids, and typically make up 10–20 mol % of plasma membrane lipids.
The Davson–Danielli model was a model of the plasma membrane of a cell, proposed in 1935 by Hugh Davson and James Danielli. The model describes a phospholipid bilayer that lies between two layers of globular proteins, which is both trilaminar and lipoprotinious. The phospholipid bilayer had already been proposed by Gorter and Grendel in 1925; however, the flanking proteinaceous layers in the Davson–Danielli model were novel and intended to explain Danielli's observations on the surface tension of lipid bi-layers.
Flippases are transmembrane lipid transporter proteins located in the membrane. They are responsible for aiding the movement of phospholipid molecules between the two leaflets that compose a cell's membrane. Flippases responses to move the lipids from outer layer of membrane to inner layer.
A cell membrane defines a boundary between a cell and its environment. The primary constituent of a membrane is a phospholipid bilayer that forms in a water-based environment due to the hydrophilic nature of the lipid head and the hydrophobic nature of the two tails. In addition there are other lipids and proteins in the membrane, the latter typically in the form of isolated rafts.
In biology, membrane fluidity refers to the viscosity of the lipid bilayer of a cell membrane or a synthetic lipid membrane. Lipid packing can influence the fluidity of the membrane. Viscosity of the membrane can affect the rotation and diffusion of proteins and other bio-molecules within the membrane, there-by affecting the functions of these things.
Cell theory has its origins in seventeenth century microscopy observations, but it was nearly two hundred years before a complete cell membrane theory was developed to explain what separates cells from the outside world. By the 19th century it was accepted that some form of semi-permeable barrier must exist around a cell. Studies of the action of anesthetic molecules led to the theory that this barrier might be made of some sort of fat (lipid), but the structure was still unknown. A series of pioneering experiments in 1925 indicated that this barrier membrane consisted of two molecular layers of lipids—a lipid bilayer. New tools over the next few decades confirmed this theory, but controversy remained regarding the role of proteins in the cell membrane. Eventually the fluid mosaic model was composed in which proteins “float” in a fluid lipid bilayer "sea". Although simplistic and incomplete, this model is still widely referenced today.
One property of a lipid bilayer is the relative mobility (fluidity) of the individual lipid molecules and how this mobility changes with temperature. This response is known as the phase behavior of the bilayer. Broadly, at a given temperature a lipid bilayer can exist in either a liquid or a solid phase. The solid phase is commonly referred to as a “gel” phase. All lipids have a characteristic temperature at which they undergo a transition (melt) from the gel to liquid phase. In both phases the lipid molecules are constrained to the two dimensional plane of the membrane, but in liquid phase bilayers the molecules diffuse freely within this plane. Thus, in a liquid bilayer a given lipid will rapidly exchange locations with its neighbor millions of times a second and will, through the process of a random walk, migrate over long distances.
A model lipid bilayer is any bilayer assembled in vitro, as opposed to the bilayer of natural cell membranes or covering various sub-cellular structures like the nucleus. They are used to study the fundamental properties of biological membranes in a simplified and well-controlled environment, and increasingly in bottom-up synthetic biology for the construction of artificial cells. A model bilayer can be made with either synthetic or natural lipids. The simplest model systems contain only a single pure synthetic lipid. More physiologically relevant model bilayers can be made with mixtures of several synthetic or natural lipids.
The presence of ethanol can lead to the formations of non-lamellar phases also known as non-bilayer phases. Ethanol has been recognized as being an excellent solvent in an aqueous solution for inducing non-lamellar phases in phospholipids. The formation of non-lamellar phases in phospholipids is not completely understood, but it is significant that this amphiphilic molecule is capable of doing so. The formation of non-lamellar phases is significant in biomedical studies which include drug delivery, the transport of polar and non-polar ions using solvents capable of penetrating the biomembrane, increasing the elasticity of the biomembrane when it is being disrupted by unwanted substances and functioning as a channel or transporter of biomaterial.
The cell membrane is a biological membrane that separates and protects the interior of a cell from the outside environment. The cell membrane consists of a lipid bilayer, made up of two layers of phospholipids with cholesterols interspersed between them, maintaining appropriate membrane fluidity at various temperatures. The membrane also contains membrane proteins, including integral proteins that span the membrane and serve as membrane transporters, and peripheral proteins that loosely attach to the outer (peripheral) side of the cell membrane, acting as enzymes to facilitate interaction with the cell's environment. Glycolipids embedded in the outer lipid layer serve a similar purpose. The cell membrane controls the movement of substances in and out of a cell, being selectively permeable to ions and organic molecules. In addition, cell membranes are involved in a variety of cellular processes such as cell adhesion, ion conductivity, and cell signalling and serve as the attachment surface for several extracellular structures, including the cell wall and the carbohydrate layer called the glycocalyx, as well as the intracellular network of protein fibers called the cytoskeleton. In the field of synthetic biology, cell membranes can be artificially reassembled.
The fences and pickets model of plasma membrane is a concept of cell membrane structure suggesting that the fluid plasma membrane is compartmentalized by actin-based membrane-skeleton "fences" and anchored transmembrane protein "pickets". This model differs from older cell membrane structure concepts such as the Singer-Nicolson fluid mosaic model and the Saffman-Delbrück two-dimensional continuum fluid model that view the membrane as more or less homogeneous. The fences and pickets model was proposed to explain observations of molecular traffic made due to recent advances in single molecule tracking techniques.
A unilamellar liposome is a spherical liposome, a vesicle, bounded by a single bilayer of an amphiphilic lipid or a mixture of such lipids, containing aqueous solution inside the chamber. Unilamellar liposomes are used to study biological systems and to mimic cell membranes, and are classified into three groups based on their size: small unilamellar liposomes/vesicles (SUVs) that with a size range of 20–100 nm, large unilamellar liposomes/vesicles (LUVs) with a size range of 100–1000 nm and giant unilamellar liposomes/vesicles (GUVs) with a size range of 1–200 µm. GUVs are mostly used as models for biological membranes in research work. Animal cells are 10–30 µm and plant cells are typically 10–100 µm. Even smaller cell organelles such as mitochondria are typically 1–2 µm. Therefore, a proper model should account for the size of the specimen being studied. In addition, the size of vesicles dictates their membrane curvature which is an important factor in studying fusion proteins. SUVs have a higher membrane curvature and vesicles with high membrane curvature can promote membrane fusion faster than vesicles with lower membrane curvature such as GUVs.
Garth L. Nicolson is an American biochemist who made a landmark scientific model for cell membrane, known as the fluid mosaic model. He is the founder of The Institute for Molecular Medicine at California, and he serves as the president, chief scientific officer and emeritus professor of molecular pathology. He is also a conjoint professor in the Faculty of Science and Technology, University of Newcastle, Australia.
Before the emergence of electron microscopy in the 1950s, scientists did not know the structure of a cell membrane or what its components were; biologists and other researchers used indirect evidence to identify membranes before they could actually be visualized. Specifically, it was through the models of Overton, Langmuir, Gorter and Grendel, and Davson and Danielli, that it was deduced that membranes have lipids, proteins, and a bilayer. The advent of the electron microscope, the findings of J. David Robertson, the proposal of Singer and Nicolson, and additional work of Unwin and Henderson all contributed to the development of the modern membrane model. However, understanding of past membrane models elucidates present-day perception of membrane characteristics. Following intense experimental research, the membrane models of the preceding century gave way to the fluid mosaic model that is accepted today.
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