The Cell

Cell, in biology, the basic membrane-bound unit that contains the fundamental molecules of life and of which all living things are composed. A single cell is often a complete organism in itself, such as a bacterium or yeast. Other cells acquire specialized functions as they mature. These cells cooperate with other specialized cells and become the building blocks of large multicellular organisms, such as animals and humans. Although cells are much larger than atoms, they are still very small. The smallest known cells are a group of tiny bacteria called mycoplasmas; some of these single-celled organisms are spheres about 0.3 micrometre in diameter, with a total mass of 10⁻¹⁴ gram—equal to that of 8,000,000,000 hydrogen atoms. Cells of humans typically have a mass 400,000 times larger than the mass of a single mycoplasma bacterium, but even human cells are only about 20 micrometres across. It would require a sheet of about 10,000 human cells to cover the head of a pin, and each human organism is composed of more than 75,000,000,000,000 cells.

This section discusses the cell both as an individual unit and as a contributing part of a larger organism. As an individual unit, the cell is capable of metabolizing its own nutrients, synthesizing many types of molecules, providing its own energy, and replicating itself in order to produce succeeding generations. It can be viewed as an enclosed vessel, within which innumerable chemical reactions take place simultaneously. These reactions are under very precise control so that they contribute to the life and procreation of the cell. In a multicellular organism, cells become specialized to perform different functions through the process of differentiation. In order to do this, each cell keeps in constant communication with its neighbours. As it receives nutrients from and expels wastes into its surroundings, it adheres to and cooperates with other cells. Cooperative assemblies of similar cells form tissues, and a cooperation between tissues in turn forms organs, which carry out the functions necessary to sustain the life of an organism.

Special emphasis is given here to animal cells, with some discussion of the energy-synthesizing processes and extracellular components peculiar to plants.

The Nature and Function of Cells

A cell is enclosed by a plasma membrane, which forms a selective barrier that allows nutrients to enter and waste products to leave. The interior of the cell is organized into many specialized compartments, or organelles, each surrounded by a separate membrane. One major organelle, the nucleus, contains the genetic information necessary for cell growth and reproduction. Each cell contains only one nucleus, whereas other types of organelles are present in multiple copies in the cellular contents, or cytoplasm. Organelles include mitochondria, which are responsible for the energy transactions necessary for cell survival; lysosomes, which digest unwanted materials within the cell; and the endoplasmic reticulum and the Golgi apparatus, which play important roles in the internal organization of the cell by synthesizing selected molecules and then processing, sorting, and directing them to their proper locations. In addition, plant cells contain chloroplasts, which are responsible for photosynthesis, whereby the energy of sunlight is used to convert molecules of carbon dioxide (CO₂) and water (H₂O) into carbohydrates. Between all these organelles is the space in the cytoplasm called the cytosol. The cytosol contains an organized framework of fibrous molecules that constitute the cytoskeleton, which gives a cell its shape, enables organelles to move within the cell, and provides a mechanism by which the cell itself can move. The cytosol also contains more than 10,000 different kinds of molecules that are involved in cellular biosynthesis, the process of making large biological molecules from small ones.

Specialized organelles are a characteristic of cells of organisms known as eukaryotes. In contrast, cells of organisms known as prokaryotes do not contain organelles and are generally smaller than eukaryotic cells. However, all cells share strong similarities in biochemical function.

The Molecules of Cells

Cells contain a special collection of molecules that are enclosed by a membrane. These molecules give cells the ability to grow and reproduce. The overall process of cellular reproduction occurs in two steps: cell growth and cell division. During cell growth, the cell ingests certain molecules from its surroundings by selectively carrying them through its cell membrane. Once inside the cell, these molecules are subjected to the action of highly specialized, large, elaborately folded molecules called enzymes. Enzymes act as catalysts by binding to ingested molecules and regulating the rate at which they are chemically altered. These chemical alterations make the molecules more useful to the cell. Unlike the ingested molecules, catalysts are not chemically altered themselves during the reaction, allowing one catalyst to regulate a specific chemical reaction in many molecules.

Biological catalysts create chains of reactions. In other words, a molecule chemically transformed by one catalyst serves as the starting material, or substrate, of a second catalyst and so on. In this way, catalysts use the small molecules brought into the cell from the outside environment to create increasingly complex reaction products. These products are used for cell growth and the replication of genetic material. Once the genetic material has been copied and there are sufficient molecules to support cell division, the cell divides to create two daughter cells. Through many such cycles of cell growth and division, each parent cell can give rise to millions of daughter cells, in the process converting large amounts of inanimate matter into biologically active molecules.

The structure of biological molecules

Cells are largely composed of compounds that contain carbon. The study of how carbon atoms interact with other atoms in molecular compounds forms the basis of the field of organic chemistry and plays a large role in understanding the basic functions of cells. Because carbon atoms can form stable bonds with four other atoms, they are uniquely suited for the construction of complex molecules. These complex molecules are typically made up of chains and rings that contain hydrogen, oxygen, and nitrogen atoms, as well as carbon atoms. These molecules may consist of anywhere from 10 to millions of atoms linked together in specific arrays. Most, but not all, of the carbon-containing molecules in cells are built up from members of one of four different families of small organic molecules: sugars, amino acids, nucleotides, and fatty acids. Each of these families contains a group of molecules that resemble one another in both structure and function. In addition to other important functions, these molecules are used to build large macromolecules. For example, the sugars can be linked to form polysaccharides such as starch and glycogen, the amino acids can be linked to form proteins, the nucleotides can be linked to form the DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) of chromosomes, and the fatty acids can be linked to form the lipids of all cell membranes.

Aside from water, which forms 70 percent of a cell's mass, a cell is composed mostly of macromolecules. By far the largest portion of macromolecules are the proteins. An average-sized protein macromolecule contains a string of about 400 amino acid molecules. Each amino acid has a different side chain of atoms that interact with the atoms of side chains of other amino acids. These interactions are very specific and cause the entire protein molecule to fold into a compact globular form. In theory, nearly an infinite variety of proteins can be formed, each with a different sequence of amino acids. However, nearly all these proteins would fail to fold in the unique ways required to form efficient functional surfaces and would therefore be useless to the cell. The proteins present in cells of modern animals and humans are products of a long evolutionary history, during which the ancestor proteins were naturally selected for their ability to fold into specific three-dimensional forms with unique functional surfaces useful for cell survival.

Most of the catalytic macromolecules in cells are enzymes. The majority of enzymes are proteins. Key to the catalytic property of an enzyme is its tendency to undergo a change in its shape when it binds to its substrate, thus bringing together reactive groups on substrate molecules. Some enzymes are macromolecules of RNA, called ribozymes. Ribozymes consist of linear chains of nucleotides that fold in specific ways to form unique surfaces, similar to the ways in which proteins fold. As with proteins, the specific sequence of nucleotide subunits in an RNA chain gives each macromolecule a unique character. RNA molecules are much less frequently used as catalysts in cells than are protein molecules, presumably because proteins, with the greater variety of amino acid side chains, are more diverse and capable of complex shape changes. However, RNA molecules are thought to have preceded protein molecules during evolution and to have catalyzed most of the chemical reactions required before cells could evolve (see below The evolution of cells).

Coupled chemical reactions

Cells must obey the laws of chemistry and thermodynamics. When two molecules react with each other inside a cell, their atoms are rearranged, forming different molecules as reaction products and releasing or consuming energy in the process. Overall, chemical reactions occur only in one direction; that is, the final reaction product molecules cannot spontaneously react, in a reversal of the original process, to reform the original molecules. This directionality of chemical reactions is explained by the fact that molecules only change from states of higher free energy to states of lower free energy. Free energy is the ability to perform work (in this case, the work is the rearrangement of atoms in the chemical reaction). When work is performed, some free energy is used and lost, with the result that the process ends at lower free energy. To use a familiar mechanical analogy, water at the top of a hill has the ability to perform the work of flowing downhill (i.e., it has high free energy), but, once it has flowed downhill, it cannot flow back up (i.e., it is in a state of low free energy). However, through another work process—that of a pump, for example—the water can be returned to the top of the hill, thereby recovering its ability to flow downhill. In thermodynamic terms, the free energy of the water has been increased by energy from an outside source (i.e., the pump). In the same way, the product molecules of a chemical reaction in a cell cannot reverse the reaction and return to their original state unless energy is supplied by coupling the process to another chemical reaction.

All catalysts, including enzymes, accelerate chemical reactions without affecting their direction. To return to the mechanical analogy, enzymes cannot make water flow uphill, although they can provide specific pathways for a downhill flow. Yet most of the chemical reactions that the cell needs to synthesize new molecules necessary for its growth require an uphill flow. In other words, the reactions require more energy than their starting molecules can provide.

Cells use a single strategy over and over again in order to get around the limitations of chemistry: they use the energy from an energy-releasing chemical reaction to drive an energy-absorbing reaction that would otherwise not occur. A useful mechanical analogy might be a mill wheel driven by the water in a stream. The water, in order to flow downhill, is forced to flow past the blades of the wheel, causing the wheel to turn. In this way, part of the energy from the moving stream is harnessed to move a mill wheel, which may be linked to a winch. As the winch turns, it can be used to pull a heavy load uphill. Thus, the energy-absorbing (but useful) uphill movement of a load can be driven by coupling it directly to the energy-releasing flow of water.

In cells, enzymes play the role of mill wheels by coupling energy-releasing reactions with energy-absorbing reactions. As discussed below, in cells the most important energy-releasing reaction serving a role similar to that of the flowing stream is the hydrolysis of adenosine triphosphate (ATP). In turn, the production of ATP molecules in the cells is an energy-absorbing reaction that is driven by being coupled to the energy-releasing breakdown of sugar molecules. In retracing this chain of reactions, it is necessary first to understand the source of the sugar molecules.

Photosynthesis: the beginning of the food chain

Sugar molecules are produced by the process of photosynthesis in plants and certain bacteria. These organisms lie at the base of the food chain, in that animals and other nonphotosynthesizing organisms depend on them for a constant supply of life-supporting organic molecules. Humans, for example, obtain these molecules by eating plants or other organisms that have previously eaten food derived from photosynthesizing organisms.

Plants and photosynthetic bacteria are unique in their ability to convert the freely available electromagnetic energy in sunlight into chemical bond energy, the energy that holds atoms together in molecules and is transferred or released in chemical reactions. The process of photosynthesis can be summarized by the following equation: (solar) energy + CO₂ + H₂O → sugar molecules + O₂.

The energy-absorbing photosynthetic reaction is the reverse of the energy-releasing oxidative decomposition of sugar molecules. During photosynthesis, chlorophyll molecules absorb energy from sunlight and use it to fuel the production of simple sugars and other carbohydrates. The resulting abundance of sugar molecules and related biological products makes possible the existence of nonphotosynthesizing life on Earth.

ATP: fueling chemical reactions

Certain enzymes catalyze the breakdown of organic foodstuffs. Once sugars are transported into cells, they either serve as building blocks in the form of amino acids for proteins and fatty acids for lipids or are subjected to metabolic pathways to provide the cell with ATP. ATP, the common carrier of energy inside the cell, is made from adenosine diphosphate (ADP) and inorganic phosphate (P_i). Stored in the chemical bond holding the terminal phosphate compound onto the ATP molecule is the energy derived from the breakdown of sugars. The removal of the terminal phosphate, through the water-mediated reaction called hydrolysis, releases this energy, which in turn fuels a large number of crucial energy-absorbing reactions in the cell. Hydrolysis can be summarized as follows: ATP +H₂O → ADP + P_i+ energy.

The formation of ATP is the reverse of this equation, requiring the addition of energy. The central cellular pathway of ATP synthesis begins with glycolysis, a form of fermentation in which the sugar glucose is transformed into other sugars in a series of nine enzymatic reactions, each successive reaction involving an intermediate sugar containing phosphate. In the process, the six-carbon glucose is converted into two molecules of the three-carbon pyruvic acid. Some of the energy released through glycolysis of each glucose molecule is captured in the formation of two ATP molecules.

The second stage in the metabolism of sugars is a set of interrelated reactions called the tricarboxylic acid cycle. This cycle takes the three-carbon pyruvic acid produced in glycolysis and uses its carbon atoms to form carbon dioxide (CO₂) while transferring its hydrogen atoms to special carrier molecules, where they are held in high-energy linkage.

In the third and last stage in the breakdown of sugars, oxidative phosphorylation, the high-energy hydrogen atoms are first separated into protons and high-energy electrons. The electrons are then passed from one electron carrier to another by means of an electron-transport chain. Each electron carrier in the chain has an increasing affinity for electrons, with the final electron acceptor being molecular oxygen (O₂). As separated electrons and protons, the hydrogen atoms are transferred to O₂ to form water. This reaction releases a large amount of energy, which drives the synthesis of a large number of ATP molecules from ADP and P_i.

Most of the cell's ATP is produced when the products of glycolysis are oxidized completely by a combination of the tricarboxylic acid cycle and oxidative phosphorylation. The process of glycolysis alone produces relatively small amounts of ATP. Glycolysis is an anaerobic reaction; that is, it can occur even in the absence of oxygen. The tricarboxylic acid cycle and oxidative phosphorylation, on the other hand, require oxygen. Glycolysis forms the basis of anaerobic fermentation, and it presumably was a major source of ATP for early life on Earth, when very little oxygen was available in the atmosphere. Eventually, however, bacteria evolved that were able to carry out photosynthesis. Photosynthesis liberated these bacteria from a dependence on the metabolism of organic materials that had accumulated from natural processes, and it also released oxygen into the atmosphere. Over a prolonged period of time, the concentration of molecular oxygen increased until it became freely available in the atmosphere. The aerobic tricarboxylic acid cycle and oxidative phosphorylation then evolved, and the resulting aerobic cells made much more efficient use of foodstuffs than their anaerobic ancestors, because they could convert much larger amounts of chemical bond energy into ATP.

The genetic information of cells

Cells can thus be seen as a self-replicating network of catalytic macromolecules engaged in a carefully balanced series of energy conversions that drive biosynthesis and cell movement. But energy alone is not enough to make self-reproduction possible; the cell must contain detailed instructions that dictate exactly how that energy is to be used. These instructions are analogous to the blueprints that a builder uses to construct a house; in the case of cells, however, the blueprints themselves must be duplicated along with the cell before it divides, so that each daughter cell can retain the instructions that it needs for its own replication. These instructions constitute the cell's heredity.

DNA: the genetic material

During the early 19th century, it became widely accepted that all living organisms are composed of cells arising only from the growth and division of other cells. The improvement of the microscope then led to an era during which many biologists made intensive observations of the microscopic structure of cells. By 1885 a substantial amount of indirect evidence indicated that chromosomes—dark-staining threads in the cell nucleus—carried the information for cell heredity. It was later shown that chromosomes are about half DNA and half protein by weight.

The revolutionary discovery suggesting that DNA molecules could provide the information for their own replication came in 1953, when American geneticist and biophysicist James Watson and British biophysicist Francis Crick proposed a model for the structure of the double-stranded DNA molecule (called the DNA double helix). In this model, each strand serves as a template in the synthesis of a complementary strand. Subsequent research confirmed the Watson and Crick model of DNA replication and showed that DNA carries the genetic information for reproduction of the entire cell.

All of the genetic information in a cell was initially thought to be confined to the DNA in the chromosomes of the cell nucleus. Later discoveries identified small amounts of additional genetic information present in the DNA of much smaller chromosomes located in two types of organelles in the cytoplasm. These organelles are the mitochondria in animal cells and the mitochondria and chloroplasts in plant cells. The special chromosomes carry the information coding for a few of the many proteins and RNA molecules needed by the organelles. They also hint at the evolutionary origin of these organelles, which are thought to have originated as free-living bacteria that were taken up by other organisms in the process of symbiosis.

RNA: replicated from DNA

It is possible for RNA to replicate itself by mechanisms related to those used by DNA, even though it has a single-stranded instead of a double-stranded structure. In early cells RNA is thought to have replicated itself in this way. However, all of the RNA in present-day cells is synthesized by special enzymes that construct a single-stranded RNA chain by using one strand of the DNA helix as a template. Although RNA molecules are synthesized in the cell nucleus, where the DNA is located, most of them are transported to the cytoplasm before they carry out their functions.

The RNA molecules in cells have two main roles. Some, the ribozymes, fold up in ways that allow them to serve as catalysts for specific chemical reactions. Others serve as messenger RNA, which provides templates specifying the synthesis of proteins. Ribosomes, tiny protein-synthesizing machines located in the cytoplasm, read the messenger RNA molecules and translate them into proteins by using the genetic code. In this translation, the sequence of nucleotides in the messenger RNA chain is decoded three nucleotides at a time, and each nucleotide triplet (called a codon) specifies a particular amino acid. Thus, a nucleotide sequence in the DNA specifies a protein provided that a messenger RNA molecule is produced from that DNA sequence. Each region of the DNA sequence specifying a protein in this way is called a gene.

By the above mechanisms, DNA molecules catalyze not only their own duplication but also dictate the structures of all protein molecules. A single human cell contains about 10,000 different proteins produced by the expression of 10,000 different genes. Actually, a set of human chromosomes is thought to contain DNA with enough information to express between 30,000 and 100,000 proteins, but most of these proteins seem to be made only in specialized types of cells and are therefore not present throughout the body.

The organization of cells

Intracellular communication

A cell with its many different DNA, RNA, and protein molecules is quite different from a test tube containing the same components. When a cell is dissolved in a test tube, thousands of different types of molecules randomly mix together. In the living cell, however, these components are kept in specific places, reflecting the high degree of organization essential for the growth and division of the cell. Maintaining this internal organization requires a continuous input of energy, because spontaneous chemical reactions always create disorganization. Thus, much of the energy released by ATP hydrolysis fuels processes that organize macromolecules inside the cell.

When a eukaryotic cell is examined at high magnification in an electron microscope, it becomes apparent that specific membrane-bound organelles divide the interior into a variety of subcompartments. Although not detectable in the electron microscope, it is clear from biochemical assays that each organelle contains a different set of macromolecules. This biochemical segregation reflects the functional specialization of each compartment. Thus, the mitochondria, which produce most of the cell's ATP, contain all of the enzymes needed to carry out the tricarboxylic acid cycle and oxidative phosphorylation. Similarly, the degradative enzymes needed for the intracellular digestion of unwanted macromolecules are confined to the lysosomes.

It is clear from this functional segregation that the many different proteins specified by the genes in the cell nucleus must be transported to the compartment where they will be used. Not surprisingly, the cell contains an extensive membrane-bound system devoted to maintaining just this intracellular order. The system serves as a post office, guaranteeing the proper routing of newly synthesized macromolecules to their proper destinations.

All proteins are synthesized on ribosomes located in the cytosol. As soon as the first portion of the amino acid sequence of a protein emerges from the ribosome, it is inspected for the presence of a short endoplasmic reticulum (ER) signal sequence. Those ribosomes making proteins with such a sequence are transported to the surface of the ER membrane, where they complete their synthesis; the proteins made on these ribosomes are immediately transferred through the ER membrane to the inside of the ER compartment. Proteins lacking the ER signal sequence remain in the cytosol and are released from the ribosomes when their synthesis is completed. This chemical decision process places some newly completed protein chains in the cytosol and others within an extensive membrane-bounded compartment in the cytoplasm, representing the first step in intracellular protein sorting.

The newly made proteins in both cell compartments are then sorted further according to additional signal sequences that they contain. Some of the proteins in the cytosol remain there, while others go to the surface of mitochondria or (in plant cells) chloroplasts, where they are transferred through the membranes into the organelles. Subsignals on each of these proteins then designate exactly where in the organelle the protein belongs. The proteins initially sorted into the ER have an even wider range of destinations. Some of them remain in the ER, where they function as part of the organelle. Most enter transport vesicles and pass to the Golgi apparatus, separate membrane-bounded organelles that contain at least three subcompartments. Some of the proteins are retained in the subcompartments of the Golgi, where they are utilized for functions peculiar to that organelle. Most eventually enter vesicles that leave the Golgi for other cellular destinations such as the cell membrane, lysosomes, or special secretory vesicles.

Intercellular communication

Formation of a multicellular organism starts with a small collection of similar cells in an embryo and proceeds by continuous cell division and specialization to produce an entire community of cooperating cells, each with its own role in the life of the organism. Through cell cooperation, the organism becomes much more than the sum of its component parts.

A fertilized egg multiplies and produces a whole family of daughter cells, each of which adopts a structure and function according to its position in the entire assembly. All of the daughter cells contain the same chromosomes and therefore the same genetic information. Despite this common inheritance, different types of cells behave differently and have different structures. In order for this to be the case, they must express different sets of genes, so that they produce different proteins despite their identical embryological ancestors.

During the development of an embryo, it is not sufficient for all the cell types found in the fully developed individual simply to be created. Each cell type must form in the right place at the right time and in the correct proportion; otherwise, there would be a jumble of randomly assorted cells in no way resembling an organism. The orderly development of an organism depends on a process called cell determination, in which initially identical cells become committed to different pathways of development. A fundamental part of cell determination is the ability of cells to detect different chemicals within different regions of the embryo. The chemical signals detected by one cell may be different from the signals detected by its neighbour cells. The signals that a cell detects activate a set of genes that tell the cell to differentiate in ways appropriate for its position within the embryo. The set of genes activated in one cell differs from the set of genes activated in the cells around it. The process of cell determination requires an elaborate system of cell-to-cell communication in early embryos.

The Cell Membrane

A thin membrane, typically between 4 and 10 nanometers (nm; 1 nm = 10₋₉ metre) in thickness, surrounds every living cell, delimiting the cell from the environment around it. Enclosed by this cell membrane (also known as the plasma membrane) are the cell's constituents, often large, water-soluble, highly charged molecules such as proteins, nucleic acids, carbohydrates, and substances involved in cellular metabolism. Outside the cell, in the surrounding water-based environment, are ions, acids, and alkalis that are toxic to the cell, as well as nutrients that the cell must absorb in order to live and grow. The cell membrane, therefore, has two functions: first, to be a barrier keeping the constituents of the cell in and unwanted substances out and, second, to be a gate allowing transport into the cell of essential nutrients and movement from the cell of waste products.

Chemical composition and membrane structure

Most current knowledge about the biochemical constituents of cell membranes originates in studies of red blood cells. The chief advantage of these cells for experimental purposes is that they may be obtained easily in large amounts and that they have no internal membranous organelles to interfere with study of their cell membranes. Careful studies of these and other cell types have shown that all membranes are composed of proteins and fatty-acid-based lipids. Membranes actively involved in metabolism contain a higher proportion of protein; thus, the membrane of the mitochondrion, the most rapidly metabolizing organelle of the cell, contains as much as 75 percent protein, while the membrane of the Schwann cell, which forms an insulating sheath around many nerve cells, has as little as 20 percent protein.

Membrane lipids

Membrane lipids are principally of two types, phospholipids and sterols (generally cholesterol). Both types share the defining characteristic of lipids—they dissolve readily in organic solvents—but in addition they both have a region that is attracted to and soluble in water. This amphiphilic property (having a dual attraction; i.e., containing both a lipid-soluble and a water-soluble region) is basic to the role of lipids as building blocks of cellular membranes. Phospholipid molecules have a head (often of glycerol) to which are attached two long fatty acid chains that look much like tails. These tails are repelled by water and dissolve readily in organic solvents, giving the molecule its lipid character. To another part of the head is attached a phosphoryl group with a negative electrical charge; to this group in turn is attached another group with a positive or neutral charge. This portion of the phospholipid dissolves in water, thereby completing the molecule's amphiphilic character. In contrast, sterols have a complex hydrocarbon ring structure as the lipid-soluble region and a hydroxyl grouping as the water-soluble region.

When dry phospholipids, or a mixture of such phospholipids and cholesterol, are immersed in water under laboratory conditions, they spontaneously form globular structures called liposomes. Investigation of the liposomes shows them to be made of concentric spheres, one sphere inside of another and each forming half of a bilayered wall. A bilayer is composed of two sheets of phospholipid molecules with all of the molecules of each sheet aligned in the same direction. In a water medium, the phospholipids of the two sheets align so that their water-repellent, lipid-soluble tails are turned and loosely bonded to the tails of the molecules on the other sheet. The water-soluble heads turn outward into the water, to which they are chemically attracted. In this way, the two sheets form a fluid, sandwichlike structure, with the fatty acid chains in the middle mingling in an organic medium while sealing out the water medium.

This type of lipid bilayer, formed by the self-assembly of lipid molecules, is the basic structure of the cell membrane. It is the most stable thermodynamic structure that a phospholipid-water mixture can take up: the fatty acid portion of each molecule dissolved in the organic phase formed by the identical regions of the other molecules and the water-attractive regions surrounded by water and facing away from the fatty acid regions. The chemical affinity of each region of the amphiphilic molecule is thus satisfied in the bilayer structure.

Membrane proteins

Membrane proteins are also of two general types. One type, called the extrinsic proteins, is loosely attached by ionic bonds or calcium bridges to the electrically charged phosphoryl surface of the bilayer. They can also attach to the second type of protein, called the intrinsic proteins. The intrinsic proteins, as their name implies, are firmly embedded within the phospholipid bilayer. Almost all intrinsic proteins contain special amino acid sequences, generally about 20- to 24-amino acids long, that extend through the internal regions of the cell membrane.

Most intrinsic and extrinsic proteins bear on their outer surfaces side chains of complex sugars, which extend into the aqueous environment around the cell. For this reason, these proteins are often referred to as glycoproteins. Some glycoproteins are involved in cell-to-cell recognition.

Membrane fluidity

One of the triumphs of cell biology during the decade from 1965 to 1975 was the recognition of the cell membrane as a fluid collection of amphiphilic molecules. This array of proteins, sterols, and phospholipids is organized into a liquid crystal, a structure that lends itself readily to rapid cell growth. Measurements of the membrane's viscosity show it as a fluid one hundred times as viscous as water, similar to a thin oil. The phospholipid molecules diffuse readily in the plane of the bilayer. Many of the membrane's proteins also have this freedom of movement, but some are fixed in the membrane by interaction with the cell's cytoskeleton. Newly synthesized phospholipids insert themselves easily into the existing cell membrane. Intrinsic proteins are inserted during their synthesis on ribosomes bound to the endoplasmic reticulum, whereas extrinsic proteins found on the internal surface of the cell membrane are synthesized on free, or unattached, ribosomes, liberated into the cytoplasm, and then brought to the membrane.

Transport across the membrane

The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. Yet the membrane is also a formidable barrier, allowing some dissolved substances, or solutes, to pass while blocking others. Lipid-soluble molecules and some small molecules can permeate the membrane, but the lipid bilayer effectively repels the many large, water-soluble molecules and electrically charged ions that the cell must import or export in order to live. Transport of these vital substances is carried out by certain classes of intrinsic proteins that form a variety of transport systems: some are open channels, which allow ions to diffuse directly into the cell; others are facilitators, which, through a little-understood chemical transformation, help solutes diffuse past the lipid screen; yet others are pumps, which force solutes through the membrane when they are not concentrated enough to diffuse spontaneously. Particles too large to be diffused or pumped are often swallowed or disgorged whole by an opening and closing of the membrane.

Behind this movement of solutes across the cell membrane is the principle of diffusion. According to this principle, a dissolved substance diffuses down a concentration gradient; that is, given no energy from an outside source, it moves from a place where its concentration is high to a place where its concentration is low. Diffusion continues down this gradually decreasing gradient until a state of equilibrium is reached, at which point there is an equal concentration in both places and an equal, random diffusion in both directions.

A solute at high concentration is at high free energy; that is, it is capable of doing more work (the work being that of diffusion) than a solute at low concentration. In performing the work of diffusion, the solute loses free energy, so that, when it reaches equilibrium at a lower concentration, it is unable to return spontaneously (under its own energy) to its former high concentration. However, by the addition of energy from an outside source (through the work of an ion pump, for example), the solute may be returned to its former concentration and state of high free energy. This coupling of work processes is, in effect, a transferal of free energy from the pump to the solute, which is then able to repeat the work of diffusion. See above Coupled chemical reactions.)

For most substances of biological interest, the concentrations inside and outside the cell are different, creating concentration gradients down which the solutes spontaneously diffuse, provided they can permeate the lipid bilayer. Membrane channels and diffusion facilitators bring them through the membrane by passive transport; that is, the changes that the proteins undergo in order to facilitate diffusion are powered by the diffusing solutes themselves. For the healthy functioning of the cell, certain solutes must remain at different concentrations on each side of the membrane; if through diffusion they approach equilibrium, they must be pumped back up their gradients by the process of active transport. Those membrane proteins serving as pumps accomplish this by coupling the energy required for transport to the energy produced by cell metabolism or by the diffusion of other solutes.

Permeation

Permeation is the diffusion, through a barrier, of a substance in solution. The rates at which biologically important molecules cross the cell membrane through permeation vary over an enormous range. Proteins and sugar polymers do not permeate at all; in contrast, water and alcohols permeate most membranes in less than a second. This variation, caused by the lipid bilayer, gives the membrane its characteristic permeability. Permeability is measured as the rate at which a particular substance in solution crosses the membrane.

For all cell membranes that have been studied in the laboratory, permeability increases in parallel with the permeant's ability to dissolve in organic solvents. The consistency of this parallel has led researchers to conclude that permeability is a function of the fatty acid interior of the lipid bilayer, rather than its phosphoryl exterior. This property of dissolving in organic solvents rather than water is given a unit of measure called the partition coefficient. The greater the solubility of a substance, the higher its partition coefficient, and the higher the partition coefficient, the higher the permeability of the membrane to that particular substance. For example, the water solubility of hydroxyl, carboxyl, and amino groups reduces their solubility in organic solvents and, hence, their partition coefficients. Cell membranes have been observed to have low permeability toward these groups. In contrast, lipid-soluble methyl residues and hydrocarbon rings, which have high partition coefficients, penetrate cell membranes more easily—a property useful in designing chemotherapeutic and pharmacological drugs.

For two molecules of the same partition coefficient, the one of greater molecular weight, or size, will in general cross the membrane more slowly. In fact, even molecules with very low partition coefficients can penetrate the membrane if they are small enough. Water, for example, is insoluble in organic solvents, yet it permeates cell membranes because of the small size of its molecules. The size selectivity of the lipid bilayer is a result of its being not a simple fluid, the molecules of which move around and past a diffusing molecule, but an organized matrix, a kind of fixed grate, composed of the fatty acid chains of the phospholipids through which the diffusing molecule must fit.

Many substances do not actually cross the cell membrane through permeation of the lipid bilayer. Some electrically charged ions, for example, are repelled by organic solvents and therefore cross cell membranes with great difficulty, if at all. In these cases special holes in the membrane, called channels, allow specific ions and small molecules to diffuse directly through the bilayer.

Membrane channels

Biophysicists measuring the electric current passing through cell membranes have found that, in general, cell membranes have a vastly greater electrical conductance than does a membrane bilayer composed only of phospholipids and sterols. This greater conductance is thought to be conferred by the cell membrane's proteins. A current flowing across a membrane often appears on a recording instrument as a series of bursts of various heights. These bursts represent current flowing through open channels, which are merely holes formed by intrinsic proteins traversing the lipid bilayer. No significant current flows through the membrane when no channel is open; multiple bursts are recorded when more than one channel is open.

A rich variety of channels has been isolated and analyzed from a wide range of cell membranes. Invariably intrinsic proteins, they contain numerous amino acid sequences that traverse the membrane, clearly forming a specific hole, or pore. Certain channels open and close spontaneously. Some are gated, or opened, by the chemical action of a signaling substance such as calcium, acetylcholine, or glycine, whereas others are gated by changes in the electrical potential across the membrane. Channels may possess a narrow specificity, allowing passage of only potassium or sodium, or a broad specificity, allowing passage of all positively charged ions (cations) or of all negatively charged ions (anions). There are channels called gap junctions that allow the passage of molecules between pairs of cells.

The gating of channels with a capacity for ion transport is the basis of the many nerve-nerve, nerve-muscle, and nerve-gland interactions underlying neurobiological behaviour. These actions depend on the electric potential of the cell membrane, which varies with the prevailing constituents in the cell's environment. For example, if a channel that admits only potassium ions is present in a membrane separating two different potassium chloride solutions, the positively charged potassium ions tend to flow down their concentration gradient through the channel. The negatively charged chloride ions remain behind. This separation of electric charges sets up an electric potential across the membrane called the diffusion potential. The size of this potential depends on, among other factors, the difference in concentrations of the permeating ion across the membrane. The cell membrane in general contains the channels of widely different ion specificities, each channel contributing to the overall membrane potential according to the permeability and concentration ratio of the ion passing through it. Since the channels are often gated, the membrane's potential is determined by which channels are open; this in turn depends on the concentrations of signaling molecules and may change with time according to the membrane potential itself.

Most cells have about a tenfold higher concentration of sodium ions outside than inside and a reverse concentration ratio of potassium ions. Free calcium ions can be 10,000 times more concentrated outside the cell than inside. Thus, sodium-, potassium-, and calcium-selective membrane channels, by allowing the diffusion of those ions past the cell membrane and causing fluctuations in the membrane's electric potential, frequently serve as transmitters of signals from nerve cells. Ion diffusion threatens to alter the concentration of ions necessary for the cell to function. The proper distribution of ions is restored by the action of ion pumps.

Facilitated diffusion

Many water-soluble molecules that cannot penetrate the lipid bilayer are too large to fit through open channels. In this category are sugars and amino acids. Some ions too do not diffuse through channels. These vital substances enter and leave the cell through the action of membrane transporters, which, like channels, are intrinsic proteins that traverse the cell membrane. Unlike channels, transporter molecules do not simply open holes in the membrane. Rather, they present sites on one side of the membrane to which molecules bind through chemical attraction. The binding site is highly specific, often fitting the atomic structure of only one type of molecule. When the molecule has attached to the binding site, then, in a process not fully understood, the transporter brings it through the membrane and releases it on the other side.

This action is considered a type of diffusion because the transported molecules move down their concentration gradients, from high concentration to low. To activate the action of the transporter, no other energy is needed than that of the chemical binding of the transported molecules. This action upon the transporter is similar to catalysis, except that the molecules (in this context called substrates) catalyze not a chemical reaction but their own translocation across the cell membrane. Two such substrates are glucose and the bicarbonate ion.

The glucose transporter

This sugar-specific transport system enables half of the glucose present inside the cell to leave within four seconds at normal body temperature. The glucose transporter is clearly not a simple membrane channel. First, unlike a channel, it does not select its permeants by size, as one type of glucose is observed to move through the system a thousand times faster than its identically sized optical isomer. Second, it operates much more slowly than do most channels, moving only 1,000 molecules per second while a channel moves 1,000,000 ions. The most important difference between a membrane channel and the glucose transporter is the conformational change that the transporter undergoes while moving glucose across the membrane. Alternating between two conformations, it moves its glucose-binding site from one side of the membrane to the other. By flipping between its two conformational states, the transporter facilitates the diffusion of glucose; that is, it enables glucose to avoid the barrier of the cell membrane while moving spontaneously down its concentration gradient. When the concentration reaches equilibrium, net movement of glucose ceases.

A facilitated diffusion system for glucose is present in many cell types. Similar systems transporting a wide range of other substrates (e.g., different sugars, amino acids, nucleosides, and ions) are also present.

The anion transporter

The best-studied of the facilitated diffusion systems is that which catalyzes the exchange of anions across the red blood cell membrane. The exchange of hydroxyl for bicarbonate ions, each ion simultaneously being moved down its concentration gradient in opposite directions by the same transport molecule, is of great importance in enhancing the blood's capacity to carry carbon dioxide from tissues to the lungs. The exchange molecule for these anions is the major intrinsic protein of red blood cells; one million of them are present on each cell, the polypeptide chain of each molecule traversing the membrane at least six times.

Secondary active transport

In some cases the problem of forcing a substrate up its concentration gradient is solved by coupling that upward movement to the downward flow of another substrate. In this way the energy-expending diffusion of the driving substrate powers the energy-absorbing movement of the driven substrate from low concentration to high. Because this type of active transport is not powered directly by the energy released in cell metabolism, it is called secondary.

There are two kinds of secondary active transport: counter-transport, in which the two substrates cross the membrane in opposite directions, and cotransport, in which they cross in the same direction.

Counter-transport

An example of this system (also called antiport) begins with the sugar transporter described above. There are equal concentrations of glucose on both sides of the cell. A high concentration of galactose is then added outside the cell. Galactose competes with glucose for binding sites on the transport protein, so that mostly galactose—and a little glucose—enter the cell. The transporter itself, undergoing a conformational change, presents its binding sites for sugar at the inner face of the membrane. Here, at least transiently, glucose is in excess of galactose; it binds to the transporter and leaves the cell as the transporter switches back to its original conformation. Thus, glucose is pumped out of the cell against its gradient in exchange for the galactose riding into the cell down its own gradient.

Many counter-transport systems operate across the cell membranes of the body. A well-studied system (present in red blood cells, nerve cells, and muscle cells) pumps one calcium ion out of the cell in exchange for two or three sodium ions. This system helps maintain the low calcium concentration required for effective cellular activity. A different system, present in kidney cells, counter-transports hydrogen ions and sodium ions in a one-for-one ratio. This is important in stabilizing acidity by transporting hydrogen ions out of the body as needed.

Co-transport

In co-transport (sometimes called symport) two species of substrate, generally an ion and another molecule or ion, must bind simultaneously to the transporter before its conformational change can take place. As the driving substrate is transported down its concentration gradient, it drags with it the driven substrate, which is forced to move up its concentration gradient. The transporter must be able to undergo a conformational change when not bound to either substrate, so as to complete the cycle and return the binding sites to the side from which driving and driven substrates both move.

Sodium ions are usually the driving substrates in the co-transport systems of animal cells, which maintain high concentrations of these ions through primary active transport. The driven substrates include a variety of sugars, amino acids, and other ions. During the absorption of nutrients, for example, sugars and amino acids are removed from the intestine by co-transport with sodium ions. After passing across the glomerular filter in the kidney, these substrates are returned to the body by the same system. Plant and bacterial cells usually use hydrogen ions as the driving substrate; sugars and amino acids are the most common driven substrates. When the bacterium Escherichia coli must metabolize lactose, it co-transports hydrogen ions with lactose (which can reach a concentration 1,000 times higher than that outside the cell).

Primary active transport

The sodium-potassium pump

Human red blood cells contain a high concentration of potassium and a low concentration of sodium, yet the plasma bathing the cells is high in sodium and low in potassium. When whole blood is stored cold under laboratory conditions, the cells lose potassium and gain sodium until the concentrations across the membrane for both ions are at equilibrium. When the cells are restored to body temperature and given appropriate nutrition, they extrude sodium and take up potassium, transporting both ions against their respective gradients until the previous high concentrations are reached. This ion pumping is linked directly to the hydrolysis of adenosine triphosphate (ATP), the cell's repository of metabolic energy (see above Coupled chemical reactions). For every molecule of ATP split, three ions of sodium are pumped out of the cell and two of potassium are pumped in.

The sodium-potassium pump extrudes one net positive charge during each cycle of ATP splitting. This flow of current induces an electric potential across the membrane that adds to the potentials brought about by the diffusion of ions through gated channels. The pump's contribution to the overall potential is important in certain specialized nerve cells.

Calcium pumps

Many animal cells can perform a primary active transport of calcium out of the cell, developing a 10,000-fold gradient of that ion. Calcium-activated ATPases have been isolated and shown to be intrinsic proteins straddling the membrane and undergoing conformational changes similar to those of the sodium-potassium-activated ATPase. When a rise in the concentration of cellular calcium results from the opening of calcium-selective channels, the membrane's calcium pumps restore the low concentration.

Hydrogen ion pumps

Hydrochloric acid is produced in the stomach by the active transport of hydrogen ions from the blood across the stomach lining, or gastric mucosa. Hydrogen concentration gradients of nearly one million can be achieved by a hydrogen-potassium-activated ATP-splitting intrinsic protein in the cells lining the stomach. Apart from its specific ion requirements, the properties of this enzyme are remarkably similar to those of the sodium-potassium-activated enzyme and the calcium-activated enzyme. Other hydrogen-pumping ATP-splitting primary active transporters occur in intracellular organelles, in bacteria, and in plant cells (see below The mitochondrion and the chloroplast). The steep gradient of hydrogen ions represents a store of energy that can be harnessed to the accumulation of nutrients or, in the case of bacterial flagella, to the powering of cell movement.

Transport of particles

In bringing about transmembrane movements of large molecules, the cell membrane itself undergoes concerted movements during which part of the fluid medium outside of the cell is internalized (endocytosis) or part of the cell's internal medium is externalized (exocytosis). These movements involve a fusion between membrane surfaces, followed by the re-formation of intact membranes.

Endocytosis and exocytosis are fundamental to the process of intracellular digestion. Food particles are taken into the cell via endocytosis into a vacuole. Lysosomes attach to the vacuole and release digestive enzymes to extract nutrients. The leftover waste products of digestion are carried to the plasma membrane by the vacuole and eliminated through the process of exocytosis.

In this process the cell membrane engulfs portions of the external medium, forms an almost complete sphere around it, and then draws the membrane-bounded vesicle, called an endosome, into the cell. Several types of endocytosis have been distinguished: in pinocytosis, the vesicles are small and contain fluid; in phagocytosis, the vesicles are larger and contain solid matter; and in receptor-mediated endocytosis, material binds to a specific receptor on the external face of the cell membrane, triggering the process by which it is engulfed. Cholesterol enters cells by the last route.

The process by which cells engulf solid matter is called phagocytosis. There are four essential steps in phagocytosis: (1) the plasma membrane entraps the food particle, (2) a vacuole forms within the cell to contain the food particle, (3) lysosomes fuse with the food vacuole, and (4) enzymes of the lysosomes digest the food particle.

In exocytosis, material synthesized within the cell that has been packaged into membrane-bound vesicles is exported from the cell following the fusion of the vesicles with the external cell membrane. The materials so exported are cell-specific protein products, neurotransmitters, and a variety of other molecules.