Membranes are the outer boundary of individual cells and of certain organelles. Plasma membranes are the selectively permeable outermost structures of cells that separate the interior of the cell from the environment. Certain molecules are permitted to enter and exit the cell through transport across the plasma membrane.
Cell membranes contain lipids and proteins that form their structure and also facilitate cellular function. For example, cell adhesion and cell signaling are cellular processes initiated by the plasma membrane. Plasma membranes also serve as attachment points for intracellular cytoskeletal proteins and for components of the extracellular matrix outside of cells.
The basic structure of cell membranes is a phospholipid bilayer (Figure 3.1). Two antiparallel sheets of phospholipids form the membrane that surrounds the contents of the cell. The layer closest to the cytosol is the inner leaflet while the layer closest to the exterior environment is the outer leaflet. Cholesterol fits between phospholipid molecules. Proteins also associate with the membrane to enable the biological functions according to the need of the particular cell. All these membrane components are important in creating the membrane and establishing a stable yet dynamic barrier to maintain the internal environment of the cell while facilitating the biological function of the cell.
FIGURE 3.1. Plasma membrane structure.
All cell membranes, including plasma membranes, organelle membranes, and intracellular vesicles (membrane enclosed structures), are composed of the same materials. The major components of all cellular membranes are lipids and proteins. Several forms of lipids exist to provide structure, support, and function for the membrane. Membrane proteins also play both structural and functional roles.
In most cell membranes, lipids are the most abundant type of macromolecule present. Plasma and organelle membranes contain between 40% and 80% lipid. These lipids provide both the basic structure and the framework of the membrane and also regulate its function. Three types of lipids are found in cell membranes: phospholipids, cholesterol, and glycolipids.
1. Phospholipids: The most abundant of the membrane lipids are the phospholipids. They are polar, ionic compounds that are amphipathic in nature. That is, they have both hydrophilic and hydrophobic components. The hydrophilic or polar portion is in the “head group” (Figure 3.2). Within the head group is the phosphate and an alcohol that is attached to it. The alcohol can be serine, ethanolamine, inositol, or choline. Names of phospholipids then include phosphatidylserine,phosphatidylethanolamine,phosphatidylinositol, and phosphatidylcholine. While all these phospholipids contain a molecule called glycerol, the membrane phospholipid sphingomyelin has the alcohol choline in its head group and contains sphingosine instead of glycerol (Figure 3.3).
FIGURE 3.2. Structures of some phospholipids.
FIGURE 3.3. Glycerol (A) and sphingosine (B) backbones in phospholipids.
The hydrophobic portion of the phospholipid is a long, hydrocarbon (structure of carbons and hydrogens) fatty acid tail. While the polar head groups of the outer leaflet extend outward toward the environment, the fatty acid tails extend inward. Fatty acids may be saturated, containing the maximum number of hydrogen atoms bound to carbon atoms, or unsaturated with one or more carbon-to-carbon double bonds. (see also LIR Biochemistry, Chapter 17). The length of the fatty acid chains and their degree of saturation impact the membrane structure.
The fatty acid chains normally undergo motions such as flexion (bending or flexing), rotation, and lateral movement (Figure 3.4). Whenever a carbon-to-carbon double bond exists, there is a kink in the chain, reducing some types of motions and preventing the fatty acids from packing tightly together. Phospholipids in plasma membranes of healthy cells do not migrate or flip-flop from one leaflet to the other. (However, during the process of programmed cell death, enzymes catalyze the movement of phosphatidylserine from the inner leaflet to the outer leaflet [see also Chapter 23].)
FIGURE 3.4. Types of motions of membrane phospholipids.
2. Cholesterol: Another major component of cell membranes is cholesterol. An amphipathic molecule, cholesterol contains a polar hydroxyl group as well as a hydrophobic steroid ring and attached hydrocarbon (Figure 3.5). Cholesterol is dispersed throughout cell membranes, intercalating between phospholipids. Its polar hydroxyl group is near the polar head groups of the phospholipids while the steroid ring and hydrocarbon tails of cholesterol are oriented parallel to those of the phospholipids (Figure 3.6). Cholesterol fits into the spaces created by the kinks of the unsaturated fatty acid tails, decreasing the ability of the fatty acids to undergo motion and therefore causing stiffening and strengthening of the membrane.
FIGURE 3.5. Structure of cholesterol.
FIGURE 3.6. Cholesterol and phospholipids in membranes.
3. Glycolipids: Lipids with attached carbohydrate (sugars), glycolipids are found in cell membranes in lower concentration than phospholipids and cholesterol. The carbohydrate portion is always oriented toward the outside of the cell, projecting into the environment. Glycolipids help to form the carbohydrate coat observed on cells and are involved in cell-to-cell interactions. They are a source of blood group antigens and also can act as receptors for toxins including those from cholera and tetanus.
While lipids form the main structure of the membrane, proteins are largely responsible for many biological functions of the membrane. For example, some membrane proteins function in transport of materials into and out of cells (see Unit III). Others serve as receptors for hormones or growth factors (see Unit IV). The types of proteins within a plasma membrane vary depending on the cell type. However, all membrane proteins are associated with membrane in one of three main ways.
1. Membrane associations of proteins: While some proteins span the membrane with structures that cross from one side to the other, others are anchored to membrane lipids and still others are only peripherally associated with the cytosolic side of a plasma membrane (Figure 3.7).
FIGURE 3.7. Protein associations with membranes.
a. Transmembrane proteins: The first category of membrane proteins is transmembrane proteins that are embedded within the lipid bilayer of the membrane with structures that extend from the environment into the cytosol. Some transmembrane proteins contain one transmembrane region while others contain several. Some hormone receptors are proteins with seven distinct membrane-spanning regions (7-pass or 7-loop transmembrane receptors). All transmembrane proteins contain both hydrophilic and hydrophobic components. These proteins are oriented with their hydrophilic portions in contact with the aqueous exterior environment and with the cytosol and their hydrophobic portions in contact with the fatty acid tails of the phospholipids. It is usually the case that proteins cross cellular membranes by adopting a structure containing one or more ? helices (see LIR Biochemistry, Chapter 2 for a discussion of protein structure).
b. Lipid-anchored proteins: Members of the second category of membrane proteins are lipid-anchored proteins that are attached covalently to a portion of a lipid without entering the core portion of the bilayer of the membrane.
Both transmembrane and lipid-anchored proteins are integral membrane proteins since they can only be removed from a membrane by disrupting the entire membrane structure.
c. Peripheral membrane proteins: Proteins in the third category are peripheral membrane proteins. These proteins are located on the cytosolic side of the membrane and are only indirectly attached to the lipid of the membrane; they bind to other proteins that are attached to the lipids. Cytoskeletal proteins, such as those involved in the spectrin membrane skeleton of erythrocytes, are examples of peripheral membrane proteins (see Chapter 4).
2. Membrane protein functions: Membrane proteins enable cells to function as members of a tissue (Figure 3.8). For example, cell adhesion molecules are proteins that extend to the surface of cells and enable cell-to-cell contact (see Chapter 2). Other membrane proteins function as ion channels and transport proteins to enable molecules to enter and exit a cell (see Unit III). Membrane proteins that are ligand receptors enable cells to respond to hormones and other signaling molecules (see Unit IV). The preceding examples of membrane proteins are of integral, transmembrane proteins whose structures span the bilayer. Lipid-anchored membrane proteins include the G proteins, which are named for their ability to bind to guanosine triphosphate (GTP) and participate in cell signaling in response to certain hormones (see Chapter 17). Peripheral membrane proteins include cytoskeletal proteins that attach to the membrane and regulate its shape and stabilize its structure (see Chapter 4). Some other peripheral membrane proteins are also involved in cell signaling and include enzymes attached to the inner membrane leaflet that are activated after a hormone binds to a protein receptor (see Chapter 17).
FIGURE 3.8. Functions of membrane proteins.
The proteins and lipids of a cellular membrane are arranged in a certain way to form a stable outer structure of the cell. The membrane components, including lipids and proteins, are not fixed rigidly into a particular location. Both can exhibit several types of motions as described previously for phospholipids (see Figure 3.4). Membrane proteins can also move laterally and can rotate. Owing to the composition and dynamic nature of membrane components, the membrane is largely fluid in nature, as opposed to solid or rigid. Despite its fluidity, the membrane structure is very stable and supportive for the cell. The arrangement of the phospholipids provides the basic structure which is then augmented by cholesterol, with functional roles played by proteins.
Membrane phospholipids are oriented with their hydrophobic fatty acid tails facing away from the polar, aqueous fluids of both the cytosol and the environment (such as blood or other cellular fluids including lymph). The hydrophilic portions of the phospholipids are oriented toward the polar environment. Two layers of phospholipids are required to achieve this structure (Figure 3.9). The phospholipids of each layer are found in opposite orientation to each other. While the polar head groups of one layer (outer leaflet) of phospholipids face the exterior, those of the other layer (inner leaflet) face the interior. A nonpolar or hydrophobic central region results where the fatty acid tails of the two layers are in contact with each other.
FIGURE 3.9. Arrangements of membrane phospholipids in a bilayer.
The fatty acid tails of all the phospholipids are structurally very similar to each other, and the identity of an individual phospholipid molecule is determined by the alcohol within its head group, as mentioned previously (Section II.A.1 above). Some phospholipids are found on the outer leaflet while others are more commonly seen on the inner leaflet. In plasma membranes of most human cells, phosphatidylcholine and sphingomyelin are in the outer leaflet oriented toward the environment, while phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol are in the inner leaflet oriented toward the cytosol (Figure 3.10).
As also mentioned previously (Section II.A.1 above), during the process of programmed cell death, phosphatidylserine is transferred enzymatically from the inner leaflet to the outer leaflet of the membrane. The presence of phosphatidylserine on the outer leaflet then triggers phagocytic removal of the dying cells, emphasizing further that the maintenance of membrane asymmetry is important for normal cell function.
FIGURE 3.10. Asymmetry of membranes.
In addition to an asymmetric distribution of phospholipids between the membrane leaflets, glycolipids are differentially arranged as well and are always on the outer leaflet with their attached carbohydrate projecting away from the cell. Glycoproteins (proteins with attached carbohydrates) are similarly oriented on the outer leaflet with carbohydrates projecting into the environment. Peripheral membrane proteins are attached only to the inner membrane leaflet, facing the cytoplasm. Therefore, the inner and outer membrane leaflets have different compositions and each is able to have functions distinct from those of the other. Cholesterol however can readily flip-flop or move from one leaflet to the other and is distributed on both sides of the membrane bilayer.
Fluid mosaic model
For several decades, the membrane model proposed by Singer and Nicholson in 1972 has been used to describe plasma membranes. The membrane is described as a fluid, owing to the ability of lipids to diffuse laterally within the plane of the membrane. The overall structure is likened to a flowing sea. And, like a mosaic, membrane proteins are dispersed throughout the membrane. Many of the membrane proteins retain the ability to undergo lateral motion and are likened to icebergs floating within the sea of lipids (Figure 3.11).
FIGURE 3.11. Fluid mosaic model.
Specialized cholesterol-enriched microdomains within cell membranes are known as lipid rafts (Figure 3.12). Fatty acid chains of phospholipids within the rafts are extended and more tightly packed. The lipid rafts are described as floating within the fluid created by the poorly ordered lipids of the surrounding portions of the membrane. Phospholipids with straight acyl chains, including glycosphingolipids, are found in lipid rafts. Functions of lipid rafts include cholesterol transport, endocytosis, and signal transduction. Three types of lipid rafts have been described including glycosphingolipid-enriched membranes (GEM), polyphosphoinositol-rich rafts, and caveolae. The caveolae are flask-shaped invaginations of cell membranes containing the protein caveolin, whose presence causes a local change in morphology of the membrane (Figure 3.13).
FIGURE 3.12. Lipid raft.
FIGURE 3.13. Caveolae.
- Plasma membranes are selectively permeable outermost structures of eukaryotic cells.
- All biological membranes have the same basic structure.
- Lipids are generally the most abundant type of macromolecule within cell membranes.
- Phospholipids and cholesterol are amphipathic lipids that form the basic structure of cell membranes.
- Proteins associated with membranes may be transmembrane, lipid anchored, or peripheral to the membrane.
- Membrane proteins function as ion channels, transport proteins, ligand receptors, and components of the cytoskeleton.
- The basic membrane structure is that of a phospholipid bilayer.
- An asymmetric distribution of phospholipids results in each side or leaflet of the membrane having distinctive characteristics.
- Lipids and proteins in the membrane are not static but retain the ability to undergo motion within the membrane.
- The fluid mosaic model describes the fluid phospholipid “sea” in which proteins appear to be distributed in a mosaic pattern and to float within the sea of the lipids.
- Membrane microdomains known as lipid rafts are membrane regions enriched in specialized lipids that function in cholesterol transport, endocytosis, and signal transduction.