Most of the fatty acids in the membrane are unsaturated because this allows the membrane to be more flexible cis bonds are bent to allow certain molecules through the membrane. However, the interaction of the hydrophobic inside of the layer acts as a barrier for ionic and polar molecules from entering the inside of the cell.
This helps to make the membrane more rigid and adds strength. The gray spheres represent the non-polar hydrocarbon chains, which are hydrophobic or water hating. The purple spheres represent individual phospholid molecules. Introduction Cell membranes are composed of two classes of molecules: lipids and proteins.
There are two common phospholipids found in the bilayer: Lecithin contains the amino alcohol, choline. Cephalins contain the amino alcohols serine or ethanolamine. Janice L. Robertson; The lipid bilayer membrane and its protein constituents. J Gen Physiol 5 November ; 11 : — In , the year the Journal of General Physiology was founded, there was little understanding of the structure of the cell membrane.
It was evident that cells had invisible barriers separating the cytoplasm from the external solution. However, it would take decades before lipid bilayers were identified as the essential constituent of membranes. It would take even longer before it was accepted that there existed hydrophobic proteins that were embedded within the membrane and that these proteins were responsible for selective permeability in cells.
With a combination of intuitive experiments and quantitative thinking, the last century of cell membrane research has led us to a molecular understanding of the structure of the membrane, as well as many of the proteins embedded within.
Now, research is turning toward a physical understanding of the reactions of membrane proteins and lipids in this unique and incredibly complex solvent environment. Organisms live and thrive in a wide range of chemical environments with varying physical conditions. Life has been found at freezing temperatures, thermal vents, extreme acidic and alkaline conditions, and a wide range of salt concentrations.
First and foremost, the membrane must be a barrier to salts, protons, and charged molecules to maintain proper biochemistry. In addition, if the membrane is capable of separating charge, like a low dielectric insulator, then it can also store electrical as well as chemical potential energy to fuel future biological work. Finally, the membrane must be capable of changing its shape to accommodate the increasingly complex requirements of biology, and therefore, it must be fluid in nature.
It is remarkable that all of the physical properties listed above are satisfied by a two-molecule-thick layer of self-assembled oil and even more amazing how proteins have evolved to function in this dramatically different physical environment. The lipid bilayer provides a robust solution for a physiological barrier, and its simplicity is a foundation for the origins of life and evolutionary diversity Schrum et al.
In this Milestones article, I review some of the key experiments that led to our current understanding of the cell membrane as a lipid bilayer that solvates proteins that span the membrane. It is a daunting task to go over this enormous body of work, and so this article presents a mere sampling of the research. For those desiring a deeper review of the history, I refer you to several other resources Tanford, ; Lombard, ; Stillwell, In this paper, I first discuss how our understanding of cell membranes went from invisible boundaries to fluid lipid bilayers.
Next, I highlight the path to identifying a new class of membrane proteins that reside and function within hydrophobic lipid bilayers.
Finally, I discuss current research of membrane proteins in lipid bilayers, highlighting the key challenges and complexities of studying proteins in a solvent environment that is self-assembling and has its own structural properties and increased chemical complexity.
The past years take us from a time when we did not know the lipid bilayer and integral membrane proteins existed to the present, where the structure of membrane proteins, even in the context of the cell membrane, is becoming more and more accessible. Throughout this time, the Journal of General Physiology has been a pivotal resource for the presentation and discussion of research that is the foundation of the field of cell membrane biophysics.
Equipped with a light microscope, Robert Hooke examined the intricate assemblies of numerous biological samples, documenting these close-up observations in his book, Micrographia Hooke, One of the samples he examined was a material that was extracted from the underlayer of bark from a cork tree. He extensively studied animal structures such as the valves of the heart and veins but did not see any similar cellular compartmentalization.
We now know that the reason he could visualize the cellular structures of cork but not animal cells was because he was seeing the dried up cell walls, easily visible by eye using a microscope. But even still, in plant cells, it was apparent that there was another invisible bounding mechanism that encapsulated the cytosolic solution of protein, salts, and small molecules. This was observed in some cells, where the protoplasm appeared to pull away from the cell wall and also contain the vacuoles and organelles within Fig.
What explained this encapsulation? The prevailing theory for hundreds of years was that the protoplasm was dense and colloidal, rich in protein and other biological molecules, which made it behave as a gel Lombard, It was proposed that when this gel came into contact with the extracellular solution, there was a hardening at the contact layer, perhaps through aggregation of the colloidal matrix. For a modern-day example of this, consider the popular molecular gastronomy technique known as spherification Fu et al.
This is a method that is being used in the food industry to produce artificial caviar or the juicy popping bubbles found in bubble tea. These spheres are constructed by dropping solutions containing a sodium salt of the carbohydrate polymer alginate into calcium chloride. At the interface, calcium binds to the alginate and stabilizes the polymer network to form a hardened shell enclosing the liquid of interest Fig.
Therefore, there is a chemical precedent for this, but the question remained whether this was the actual mechanism of encapsulation in biological cells. In the second half of the 19th century, a simple experimental idea would introduce a new hypothesis about the bounding mechanism of cells Tanford, ; Lombard, ; Stillwell, Conversely, when the cell was placed in a hypotonic solution, the cytosol would expand to the point of bursting.
They referred to these experiments as plasmolysis studies Fig. Finally, they demonstrated that vacuoles, when isolated from the cell, followed the same behavior, and the volume changes here were reversible.
Wilhelm Pfeffer continued these studies and proposed that a skin, or plasma membrane, existed that covered the exposed surface of the protoplasm Pfeffer, At that time, he suggested this membrane was similar to artificial copper ferrocyanide membranes that had been recently discovered by Moritz Traube Traube, These were simple studies, ones that any young student can carry out today, yet the implications of the findings were profound.
The results provided evidence that the barrier acted like an invisible skin, selectively allowing for the passage of water in and out of the cell, although limiting the permeability of salts and sugars.
The early days of plasmolysis research were limited to qualitative visualization of changes under a microscope. Some studies aimed to quantify the changes by isolating the cells and weighing them before and after the osmotic stress, which sounds like a challenging task. However, Charles E. Overton would contribute significantly to our understanding of the membrane barrier by applying the osmometric technique with the understanding that the total osmotic pressure is equal to the sum of partial pressures in solution Kleinzeller, With this improved resolution in hand, he could apply a quantitative and extensive approach to plasmolysis studies.
Over a short period of time, from to , he studied nearly different compounds for setting the osmotic gradient, including salts, sugars, and nonpolar molecules Overton, ; Kleinzeller, , Using his large body of quantitative data, he built a physical model of the cell membrane to explain his observations, modeled after gas laws that were being developed at the same time.
He proposed that the lack of the change in the cell volume was caused by the free equilibration of nonpolar or lipoid-like molecules across the cell membrane. With this, he postulated that the cell membrane itself must be composed of similar nonpolar molecules to support the free partitioning of these substances and at the same time provide a barrier to salts and sugars.
Most surprisingly, he even proposed that cholesterol and phospholipids could be candidates for the nonpolar chemicals composing the membrane. Finally, he investigated a series of nonpolar molecules that were well known for their activity in humans: general anesthetics. In parallel research with Hans Horst Meyer, they both found that the propensity for an anesthetic to partition into olive oil strongly correlated with its efficacy in the clinical setting Meyer, ; Overton, , supporting the idea of a lipid-filled nonpolar barrier to cells Fig.
The work of Overton and Meyer is a fine example of biophysics-based translational research at the turn of the 19th century. In , Alan Finkelstein clarified these findings by carrying out a series of experiments studying the partitioning and diffusion of different solutes into nonpolar solvents.
By studying solutes of different structures and sizes, he demonstrated that membrane permeability follows a coupled solubility—diffusion mechanism Finkelstein, At the same time as the plasmolysis studies, the study of surface physics was developing Roberts, Benjamin Franklin, in the late s, was one of the first to describe the behavior of a drop of oil to spread out thinly on a body of water Tanford, This work sparked the interest of Agnes Pockels, a young woman who spent her time at home, caring for her parents and the household.
Although she did not formally attend school, her brother was a university student studying physics, and she was exposed to the literature and textbooks that he would bring home.
In her daily kitchen work, she would observe the behavior of oil on water while she washed the pots and pans, and this made her wonder about the molecular structure and physical properties of these thin films. With clear passion and determination, she built an apparatus for measuring the surface tension of the thin oil films on water out of the kitchen pans that she was so familiar with.
She contacted Lord Rayleigh, and in , he helped her to publish her first independent paper and one of the first studies of surface tension Pockels, The development of the Langmuir trough provided the key equipment for high-resolution investigations of the structure of cell membranes. The choice of erythrocytes was key to this experiment because these cells do not contain major organelles, and so the lipid fraction extracted would be expected to represent only the plasma membrane.
They used the Langmuir trough to measure the surface area of the lipid molecules composing the cell membrane Gorter and Grendel, and discovered that the area was exactly half of that expected if the molecules formed a monolayer. This led them to conclude that the cell membrane was a lipid bilayer, formed by two layers of oil molecules.
This was the first proposal of such a structure and somewhat serendipitous considering their experimental approach was far from robust. Changes in the lipid extraction methods and surface pressure dependencies can alter the conclusions of the experiment Bar et al. Still, the seed of the idea of the cell membrane as a lipid bilayer structure was planted, which was a sufficient starting point. In the same year, Hugo Fricke measured the electrical capacitance of intact erythrocytes in suspension Fricke, Perhaps more importantly, this experiment demonstrated that the cell membrane was an electrical barrier.
In , James Frederic Danielli and Hugh Davson compiled the many results from Fricke, Gorter, and Grendel and others to develop the paucimolecular model Danielli and Davson, , i. In the Danielli and Davson model, they propose a bilayer of ampipathic lipoid molecules filled with a nonpolar lipoid center Fig. On either side of the membrane is a protein layer at least one molecule thick adsorbed onto the lipoid surface because it was believed that proteins could not stably exist inside the membrane.
In their model, it was these protein layers that were responsible for selective permeability, and they could form structures spanning the membrane to enable the passage of salts and sugars. This model consolidated many of the physical findings of the cell membrane, but the idea of the membrane structure as a lipid bilayer remained under heavy debate for many decades.
This changed in , when J. David Robertson was studying the ultrastructure of myelin sheaths at the Nodes of Ranvier by electron microscopy.
To improve resolution, he applied potassium permanganate KMnO 4 to stain structures, which highlighted a common trilaminar unit—two dark lines separated by a light center—that was observed at the plasma membrane boundary and encapsulating every organelle Robertson, He interpreted the dark lines as the adsorbed protein layers and the light center as the lipoid, similar to the model of Danielli and Davson.
The observation of the same structure being visible for all cellular compartments led him to propose the unit membrane model Fig. At that time, he even asserted that all membranes within a cell were in contact with one another, forming one continuous barrier.
Although this idea is incorrect, the main point is that the lipid bilayer structure is something that is ubiquitous within biology, and it is capable of combining and fusing under the right conditions. Rather, they are usually bound to other proteins in the membrane. Some peripheral proteins form a filamentous network just under the membrane that provides attachment sites for transmembrane proteins. Other peripheral proteins are secreted by the cell and form an extracellular matrix that functions in cell recognition.
In contrast to prokaryotes, eukaryotic cells have not only a plasma membrane that encases the entire cell, but also intracellular membranes that surround various organelles. In such cells, the plasma membrane is part of an extensive endomembrane system that includes the endoplasmic reticulum ER , the nuclear membrane, the Golgi apparatus , and lysosomes. Membrane components are exchanged throughout the endomembrane system in an organized fashion.
For instance, the membranes of the ER and the Golgi apparatus have different compositions, and the proteins that are found in these membranes contain sorting signals, which are like molecular zip codes that specify their final destination.
Mitochondria and chloroplasts are also surrounded by membranes, but they have unusual membrane structures — specifically, each of these organelles has two surrounding membranes instead of just one. The outer membrane of mitochondria and chloroplasts has pores that allow small molecules to pass easily.
The inner membrane is loaded with the proteins that make up the electron transport chain and help generate energy for the cell. The double membrane enclosures of mitochondria and chloroplasts are similar to certain modern-day prokaryotes and are thought to reflect these organelles' evolutionary origins. This page appears in the following eBook. Aa Aa Aa. Cell Membranes. Figure 1: The lipid bilayer and the structure and composition of a glycerophospholipid molecule.
A The plasma membrane of a cell is a bilayer of glycerophospholipid molecules. Figure 2: The glycerophospholipid bilayer with embedded transmembrane proteins. What Do Membranes Do? Figure 3: Selective transport. Specialized proteins in the cell membrane regulate the concentration of specific molecules inside the cell.
Figure 4: Examples of the action of transmembrane proteins. Transporters carry a molecule such as glucose from one side of the plasma membrane to the other. How Diverse Are Cell Membranes? Membranes are made of lipids and proteins, and they serve a variety of barrier functions for cells and intracellular organelles.
Membranes keep the outside "out" and the inside "in," allowing only certain molecules to cross and relaying messages via a chain of molecular events. Cell Biology for Seminars, Unit 3.
Topic rooms within Cell Biology Close. No topic rooms are there. Or Browse Visually. Student Voices. Creature Cast. Simply Science. As it happens, Gortner and Grendel made some errors in their experiment.
They failed to completely extract all the lipids from the cells, and they also underestimated the total surface area of the individual red blood cells. However, because these two errors canceled each other out, their final conclusions turned out to be correct, regardless of their miscalculations. Thereafter, the idea of a lipid bilayer became the basis for future models of membrane structure. Sadava When the use of electron microscopy started to allow examination of the plasma membrane at high resolution, people noticed that the image clearly showed three layers, not two.
In a key paper, Stoeckenius provided clear pictures of the three-layer structure. He then described in both words and diagrams how the lipid bilayer results in a three-layer image.
As it turns out, the inner and outer edges of the bilayer have a different composition than the interior. Under the view of the electron microscope, the outsides of the lipid bilayer show up as two darker layers, whereas the hydrophobic interior stains less densely, thus showing three apparent "layers" outside layers are represented as blue in Figure 1C. The first clues to lipid bilayer structure came from results with red blood cell membranes. The ultimate discovery that the plasma membrane is a lipid bilayer with hydrophobic and hydrophilic properties changed the way this structure was viewed.
Its semipermeable and liquid nature provided the groundwork for understanding both its physical and biological properties.
Edidin, M. Lipids on the frontier: a century of cell-membrane lipids Nature Reviews : Molecular Cell Biology 4 : — Gortner, E. On bimolecular layers of lipoids on the chromacytes of blood. Journal of Experimental Medicine 41 , — Langmuir, I. The constitution and fundamental properties of solids and liquids II: Liquids. Journal of the American Chemical Society 39 , — Overton, E. The probable origin and physiological significance of cellular osmotic properties.
Vierteljahrschrift der Naturforschende gesselschaft 44 , 88— In Biological Membrane Structure , trans. Park, R. Boston: Little Brown, Sadava, D. Cell Biology, Organelle Structure and Function. Boston: Jones and Bartlett, Stoeckenius, W.
Structure of the plasma membrane: An electron-microscope study. Circulation 26 , — Cell Membranes. Microtubules and Filaments. Endoplasmic Reticulum, Golgi Apparatus, and Lysosomes. Plant Cells, Chloroplasts, and Cell Walls.
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