Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intracellular and Intercellular Communication
Membranes: Structure, Assembly, and Function
Membrane Proteins

Bilayer-Associated Proteins

Membrane Phospholipids act as a solvent for Membrane Proteins, providing a microenvironment in which the latter can function. Of the 20 Amino Acids found in proteins, six are highly hydrophobic due to the side chains attached to the a-carbon atom, several are weakly hydrophobic, and the rest are hydrophilic. As we saw in Chapter 5, The formation of an a-helix minimizes the Structure/106.html">Hydrophobicity of the peptide groups themselves. Thus, proteins can form an integral whole with the membrane. For this to happen, their hydrophilic regions must protrude from the membrane into The Cell interior and exterior, while their hydrophobic regions span the Hydrophobic core of the bilayer. Indeed, those Regions of the protein molecules that are embedded in the membrane contain a high proportion of hydrophobic Amino Acids and are characterized by a high content of a-helices or β-sheets.

The number of different proteins in a membrane varies from 6–8 in the sarcoplasmic reticulum to more than 100 in The Plasma Membrane. These include Enzymes, transport proteins, structural proteins, Antigens (i.e., proteins that determine histocompatibility), and receptors for various molecules. Since each membrane is characterized by its own unique set of proteins, one cannot speak of a single typical Membrane Structure. Table 42.2 summarizes the enzymatic activities inherent to certain types of membranes.

Class="center">Table 42.2. Enzyme Markers of Various Membranes ¹⁾

¹⁾ Membranes are rich in proteins, many of which exhibit enzymatic activity. Certain enzymes are localized in specific membranes and can thus serve as markers during the purification of these membranes.

Membranes are dynamic structures.

Membrane proteins and Lipids are constantly being renewed. The turnover rates of different lipids, like those of different proteins, vary over a wide range. The membranes themselves can turn over even faster than any of their individual components. This issue will be discussed in more detail in the section dedicated to endocytosis.

Membrane Asymmetry

Asymmetry is an essential property of membranes and appears to be partly related to the uneven distribution of proteins within the membrane. Transmembrane asymmetry can also arise from the distinct localization of CARBOHYDRATES associated with membrane proteins. In addition, specific enzymes may be located exclusively on either the outer or inner surface of the membrane; this applies to both mitochondrial and Plasma Membranes.

Membranes also exhibit local asymmetry. In some cases (e.g., in the brush border of mucosal Cells), this is manifested on an almost macroscopic level. In other cases (e.g., in the regions of Gap Junctions, tight junctions, and synapses, which occupy a very small fraction of the membrane area), the areas of local asymmetry are quite small.

Asymmetry is also observed in the distribution of phospholipids between the outer and inner leaflets of membranes (transverse asymmetry). For instance, Choline-containing phospholipids (phosphatidylcholine and sphingomyelin) are located predominantly in the outer molecular layer, whereas aminophospholipids (phosphatidylserine and phosphatidylethanolamine) are concentrated mainly in the inner layer. Cholesterol is usually present in higher amounts in the outer layer than in the inner one. Obviously, if such asymmetry exists in principle, the transverse mobility (flip-flop) of membrane phospholipids must be restricted. Indeed, phospholipids in synthetic bilayers are characterized by an exceptionally low rate of translocation — the lifetime of asymmetry can be measured in days or weeks. However, upon the artificial incorporation of certain membrane proteins into synthetic bilayers, such as the erythrocyte protein Glycophorin, the frequency of phospholipid flip-flop transitions can increase a hundredfold.

The mechanisms underlying the asymmetric Distribution of lipids have not yet been fully elucidated. The enzymes involved in phospholipid synthesis are localized on the cytoplasmic side of microsomal vesicle membranes. Thus, it can be hypothesized that translocases exist which transport specific phospholipids from the inner leaflet to the outer leaflet. Furthermore, specific proteins capable of preferentially binding particular phospholipids may be present in both leaflets, resulting in their asymmetric distribution.

Integral and Peripheral Membrane Proteins

The majority of membrane proteins are integral components of membranes (interacting directly with phospholipids); almost all thoroughly studied proteins have a length exceeding 5–10 nm, which corresponds to the thickness of the bilayer. These integral proteins typically adopt globular, amphiphilic structures. Both of their ends are hydrophilic, while the region spanning the core of the bilayer is hydrophobic. Once The structure of integral membrane proteins was established, it became clear that some of them (e.g., transport protein molecules) can traverse the bilayer multiple times, as shown in Fig. 42.7.

Integral proteins are distributed asymmetrically within the bilayer (Fig. 42.8). If a membrane containing asymmetrically distributed integral proteins is solubilized in a detergent, and the detergent is subsequently removed slowly, the phospholipids and integral proteins will self-assemble to form a membrane structure, but the proteins within it will no longer be specifically oriented. Thus, the asymmetric orientation of at least some proteins in the membrane can be dictated by their insertion into The Lipid Bilayer. The outer hydrophilic portion of the amphiphilic protein, which is synthesized inside the cell, must then cross the hydrophobic layer of the membrane and ultimately end up on the outside. We will discuss the MOLECULAR MECHANISMS OF membrane Organization later.

Fig. 42.7. Proposed model of the human glucose transporter. The transporter is postulated to cross the membrane 12 times. The membrane-spanning segments can form amphiphilic a-helices with amide and hydroxyl side chains, and presumably bind glucose or form a channel for its transport. The amino and carboxyl termini are located on the cytoplasmic surface. (From Mueckler et al.: Sequence and structure of a human glucose transporter. Science, 1985, 229, 941; reproduced with permission.)

Peripheral proteins do not interact directly with phospholipids in the bilayer; instead, they form weak bonds with the hydrophilic regions of specific integral proteins. For example, ankyrin, a peripheral protein, is bound to band 3, an integral protein of The erythrocyte membrane. Spectrin, which forms the skeletal network of the erythrocyte membrane, is in turn bound to ankyrin and thus plays a crucial role in maintaining the biconcave shape of THE RED Blood cell. Immunoglobulin molecules act as integral Proteins of the plasma membrane and are released only along with a small membrane fragment. Many Hormone Receptors are integral proteins, and the specific polypeptide Hormones that bind to these receptors can therefore be considered peripheral proteins. Such peripheral proteins, acting as Peptide Hormones, may even determine the distribution of their receptors (integral proteins) within the plane of the bilayer (see below).