BIOCHEMISTRY: A TEXTBOOK FOR UNIVERSITIES - E. S. Severin - 2004

SECTION 1. STRUCTURE, PROPERTIES, AND FUNCTIONS OF PROTEINS

VI. Protein Diversity

The Human Body contains over 50,000 individual Proteins, which differ in their Primary Structure, conformation, Active Site architecture, and Functions. Proteins are built from 20 chemically distinct Amino Acids, each of which can occupy any position within the polypeptide chain. Furthermore, proteins vary in the total number of amino acids they contain.

However, under physiological conditions, most such proteins would be expected to adopt multiple Conformations with approximately equal energy, yet distinct chemical Properties and functions. Therefore, Evolutionary Processes presumably selected only a small fraction of possible protein variants capable of adopting a single, stable conformation.

Thus, the Introduction/19.html">Primary structure of evolutionarily selected proteins ensures the exceptional stability of one specific conformation, which ultimately dictates the Functional Characteristics of the given protein.

The Emergence of novel proteins is frequently associated with minor structural modifications in pre-existing proteins. Moreover, thanks to genetic mechanisms that will be discussed in Section 4, a protein with advantageous properties—or the core structural domain of such a protein—can become integrated into other proteins. Proteins that share similar Amino acid sequences and related functions are grouped together into Protein Families.

A. Protein Classification

To date, there is no universal and comprehensive classification system that accounts for all protein parameters. Existing classifications are typically based on a single criterion. For instance, proteins may be classified:

✵ by molecular shape (globular or fibrous);

✵ by molecular weight (low molecular weight, high molecular weight, etc.);

✵ by chemical composition (presence or absence of a non-protein moiety);

✵ by biological function (transport, defensive, structural proteins, etc.);

✵ by intracellular localization (nuclear, cytoplasmic, lysosomal, etc.);

✵ by localization within the Organism (Blood, Liver, Heart proteins, etc.);

✵ by The ability to adaptively regulate their Abundance: proteins synthesized at a constant rate (constitutive) and proteins whose synthesis can be upregulated by environmental stimuli (inducible);

✵ by their half-Life in the Cell (ranging from rapidly turning over proteins with a T¹/₂ of less than 1 h, to very slowly turning over proteins whose T¹/₂ is measured in weeks and months);

✵ by Sequence Homology in primary structure and related functions (protein families).

B. Classification of Proteins by Molecular Shape

This is one of the oldest classification systems, dividing proteins into two groups: globular and fibrous. Globular proteins are defined as those in which The ratio of the longitudinal to the transverse axis does not exceed 1:10, and is typically 1:3 or 1:4; in other words, the protein molecule has an ellipsoidal shape. The majority of individual human proteins belong to globular proteins. They possess a compact structure and, largely due to the burying of hydrophobic residues within the interior of the molecule, are readily soluble in Water. Clear Examples of the Structure and function of globular proteins are the Myoglobin and Hemoglobins examined above.

Fibrous proteins possess an elongated, thread-like structure in which the ratio of the longitudinal to the transverse axis exceeds 1:10. Fibrous proteins include collagens, Elastin, and keratin, which perform structural functions in the human body, as well as Myosin, which is involved in Muscle contraction, and fibrin, a protein of the Blood Coagulation SYSTEM. Using collagens and elastin as examples, we will examine the Structural Features of these proteins and the relationship between their structure and function.

1. STRUCTURE AND FUNCTIONS of Collagens

Collagens represent a family of related fibrous proteins secreted by Connective Tissue Cells. They are the most abundant proteins not only in the Extracellular matrix, but in the body as a whole, accounting for approximately 1/4 of all proteins in the human body. In the extracellular matrix, Collagen molecules assemble into polymers known as collagen fibrils (described in greater detail in Section 15). Collagen fibrils exhibit immense tensile strength and are virtually inextensible. They can withstand loads up to 10,000 times their own weight. In terms of tensile strength, collagen fibrils surpass steel wire of the same cross-sectional area. Consequently, a high abundance of collagen fibers—composed of collagen fibrils—is a major component of Skin, tendons, Cartilage, and bone.

The unusual mechanical properties of collagens stem from their primary and spatial structures. Collagen molecules consist of three polypeptide chains, designated as α-chains. More than 20 different α-chains have been identified, the majority of which consist of 1,000 amino acid residues, though the chains differ slightly in their Amino Acid Sequence. Collagens may comprise three identical or different chains.

The primary structure of collagen α-chains is unusual because every third amino acid residue in the polypeptide chain is Glycine, approximately ¹/₄ of The amino acid residues are Proline or 4-hydroxyproline, and about 11% are Alanine. Amino acids such as Cysteine and Tryptophan are entirely absent in collagen, while Histidine, Methionine, and Tyrosine are present in very small amounts. The primary STRUCTURE OF THE collagen α-chain also contains an Unusual amino acid, hydroxylysine. The polypeptide chain of collagen can be visualized as a repeating sequence of Gly-X-Y triplets, where X and Y can be any amino acid, though proline most frequently occupies the X position, and hydroxyproline or hydroxylysine occupies the Y position. Each of these amino acids plays a critical role in The formation of collagen fibrils.

Due to its structure, proline introduces bends into the polypeptide chain, stabilizing a left-handed helical conformation. There are 3 amino acid residues per turn of the helix, rather than 3.6, which is typical for the Secondary structure of globular proteins. The helix of the collagen peptide chain is stabilized not by Hydrogen Bonds (since proline does not form them), but by the steric repulsion forces of the pyrrolidine rings in the proline residues. As a result, the distance between amino acid residues along the helical axis increases, making it more extended compared to the tightly wound α-Helix of globular proteins.

The coiled polypeptide chains intertwine to form a three-stranded right-handed superhelical molecule, often referred to as tropocollagen (Fig. 1-41). The chains are held together by hydrogen bonds formed between the amino and carboxyl groups of the peptide backbones of the different polypeptide chains comprising the triple-helical molecule. The "rigid" amino acids—proline and hydroxyproline—restrict the Rotation of the polypeptide backbone, thereby increasing the Stability of the triple helix. Glycine, having a hydrogen atom instead of a side chain, is always located at the intersection points of the chains; the absence of a side chain allows the chains to pack closely together.

Class="center">Fig. 1-41. Structure of the tropocollagen molecule (fragment).

As a result of this twisting of the polypeptide backbones and the presence of an elongated structure, the other two side chains from the Gly-X-Y amino acid triad end up on the outer surface of the tropocollagen molecule. Certain complementary regions of tropocollagen molecules can associate with one another to form collagen fibrils, and these regions are arranged such that one tropocollagen strand is staggered relative to the other by approximately 1/4 (Fig. 1-42). Ionic, hydrogen, and Hydrophobic bonds are formed between the amino acid side chains.

Fig. 1-42. Structure of a collagen fibril (fragment).

Modified amino acids—hydroxyproline and hydroxylysine—play a crucial role in the formation of collagen fibrils. The hydroxyl groups of hydroxyproline in adjacent tropocollagen chains form hydrogen bonds that strengthen The structure of collagen fibrils. Lysine and hydroxylysine side chains are essential for forming strong covalent cross-links between tropocollagen molecules, further reinforcing the collagen fibril structure. In addition, carbohydrate residues can be attached to the hydroxyl group of hydroxylysine (collagen glycosylation), the function of which remains unclear.

Thus, the amino acid sequence of collagen polypeptide chains allows for the formation of a structure with unique mechanical properties and immense tensile strength. Alterations in the primary structure of collagen can lead to hereditary disorders (see Section 15).

2. Structure and Function of Elastin

Unlike collagen, which forms rigid fibrils capable of withstanding high loads, elastin (also an extracellular matrix protein) exhibits rubber-like properties. Elastin fibers found in lung tissue, blood vessel walls, and elastic ligaments can be stretched several times their resting length, yet they return to their coiled conformation once the load is removed.

Elastin consists of about 800 amino acid residues, predominantly amino acids with nonpolar side chains, such as glycine, valine, and alanine. Elastin contains a fair amount of proline and lysine, but only a small amount of hydroxyproline; hydroxylysine is completely absent.

The presence of numerous hydrophobic side chains prevents the formation of a stable globular structure; consequently, elastin polypeptide chains do not form regular secondary and tertiary structures, but instead adopt various conformations in the extracellular matrix with roughly equal Free energy (Fig. 1-43). This is a prime example of a primary structure where the absence of a single stable, ordered conformation gives rise to the protein's essential functional properties.

The Structural and functional features of elastin are discussed in more detail in Section 15.

Fig. 1-43. Random conformations of the elastin molecule.

C. Classification of Proteins by Chemical Structure

1. Simple Proteins

Some proteins consist exclusively of polypeptide chains composed of amino acid residues. They are called "simple proteins." Examples of simple proteins include Histones, the major Chromatin proteins; they contain a high proportion of lysine and Arginine residues, whose side chains carry a positive charge (histones are described in more detail in Section 4). Elastin, the extracellular matrix protein discussed above, is also classified as a simple protein.

2. Conjugated Proteins

However, a great many proteins contain, In addition to polypeptide chains, a non-protein moiety attached to the protein via weak or covalent bonds. This non-protein component may be represented by Metal Ions or various low- or high-molecular-weight organic molecules. Such proteins are termed "conjugated proteins." The non-protein moiety firmly bound to the protein is known as the prosthetic group.

Prosthetic groups can be substances of diverse chemical nature. For instance, proteins combined with heme are called Hemoproteins. In addition to the previously discussed hemoglobins and myoglobin, hemoproteins include Enzymes such as Cytochromes, catalase, and peroxidase. Heme, when attached to different protein structures, performs functions characteristic of each specific protein (for example, transporting O₂ in Hemoglobin, and transferring electrons in cytochromes).

Proteins combined with a phosphoric acid residue are called Phosphoproteins. Phosphate residues are attached via ester bonds to the hydroxyl groups of Serine, Threonine, or tyrosine through the action of enzymes called protein Kinases.

Carbohydrate residues are frequently incorporated into proteins, conferring additional Specificity and often reducing their Rate of Enzymatic proteolysis. Such proteins are designated as Glycoproteins. Many Blood Plasma Proteins, as well as cell-surface receptor proteins, belong to glycoproteins.

Proteins functioning in complex with Lipids are called Lipoproteins, and those complexed with metals are termed Metalloproteins.

A complex protein consisting of a protein moiety (apoprotein) and a non-protein moiety (prosthetic group) is called a "holoprotein."

G. Functional Classification of proteins

Proteins perform a wide variety of biological functions within cells. Based on the similarity of their functions, they can be divided into the following major groups.

1. Enzymes

Enzymes are specialized proteins that accelerate Chemical Reactions. Thanks to enzymes, reaction rates within The Cell increase millions of times over. Because enzymes, like all proteins, possess an active site, they specifically bind a particular Ligand (or a group of similar ligands) and catalyze a specific type of chemical transformation of that molecule. Currently, about 2,000 different enzymes are known that accelerate various chemical reactions. For example, the proteolytic enzyme Trypsin cleaves peptide bonds in proteins formed by the carboxyl group of basic amino acids—arginine or lysine. The enzyme Ribonuclease cleaves the phosphoester bond between NUCLEOTIDES in a polynucleotide chain.

Due to the set of enzymes present in cells, the transformations of incoming substances proceed not chaotically, but in strictly defined directions.

2. Regulatory proteins

Regulatory proteins include a large group of protein Hormones Involved in maintaining the constancy of the body's internal environment by acting on specific target cells. For example, the hormone Insulin is released into the blood when blood glucose concentrations rise after a meal and, by stimulating glucose utilization by cells, lowers the glucose concentration back to normal, thereby restoring Homeostasis.

In addition, regulatory proteins include those whose binding to other proteins or cellular structures regulates their function. For instance, the protein calmodulin in a complex with four Ca²⁺ ions can bind to certain enzymes, altering their activity.

Regulatory DNA-binding proteins, by binding at specific moments to specific DNA sites, can regulate the rate at which Genetic information is transcribed (these are described in Section 4).

3. Receptor proteins

Signaling molecules (hormones, Neurotransmitters) exert their effects on intracellular processes through interaction with specific receptor proteins. Thus, hormones circulating in the blood find target cells and affect them by specifically binding to receptor proteins, which are typically embedded in The cell membrane. For hydrophobic regulatory molecules that cross the cell membrane, receptors are localized in the Cell Cytoplasm.

4. Transport proteins

Many blood proteins participate in The transport of specific ligands from one organ to another. Molecules that are poorly soluble in water are often transported in complexes with proteins. For example, the Blood Plasma protein albumin transports Fatty acids and bilirubin (a heme breakdown product), while erythrocyte hemoglobin participates in the transport of O₂ from the Lungs to Tissues. Steroid Hormones are carried in the blood by specific transport proteins.

Transport proteins are also involved in moving hydrophilic substances across hydrophobic membranes. Because transport proteins exhibit specific binding to ligands, their Complement in the cell membrane determines which hydrophilic molecules can enter a given cell. Glucose, amino acids, ions, and other molecules enter the cell with the help of carrier proteins.

5. Structural proteins

Certain proteins, strategically located within tissues, impart shape, provide structural support, and determine the mechanical properties of those tissues. For instance, as mentioned above, the major component of cartilage and tendons is the fibrous protein collagen, which possesses high tensile strength. Another structural protein, elastin, due to its unique architecture, provides certain tissues with the ability to stretch in all directions (such as Blood Vessels and lungs).

6. Defensive proteins

Some proteins, notably IMMUNOGLOBULINS, have the ability to recognize and bind foreign molecules, Viral Particles, and Bacteria, resulting in their neutralization. Furthermore, a complex consisting of a foreign particle and an immunoglobulin is readily recognized and destroyed by cells of The Immune System.

Proteins of the blood coagulation system, such as fibrinogen and Thrombin, also possess protective properties. They participate in the formation of a blood clot that seals a damaged vessel and prevents blood loss.

7. Contractile proteins

When performing their functions, certain proteins endow the cell with the ability to either contract or move. These proteins include Actin and myosin—fibrous proteins involved in Skeletal Muscle contraction. Another example is tubulin, which builds cellular Organelles known as microtubules. Microtubules regulate the segregation of chromatids during Cell Division. Microtubules are also essential components of Cilia and flagella, which cells use for locomotion.

However, there is A large number of proteins with unique functions that do not fit into this rather simple classification.

D. Families of related proteins

During the course of evolution within a single biological species, Amino Acid Substitutions can give rise to different proteins that perform related functions and share homologous amino acid sequences. Sequences are termed homologous when they share many features in common. They contain the same amino acids—referred to as invariant residues—at many positions, while some positions may harbor different amino acid residues with similar physicochemical properties.

These proteins have strikingly similar conformations: the number and relative arrangement of α-helices and/or β-structures, as well as most of the turns and bends of The polypeptide chains, are similar or identical. Such proteins, featuring homologous Regions of the polypeptide chain, similar conformations, and related functions, are grouped into protein families.

An example of a family of related proteins is the myoglobin family, which includes, in addition to myoglobin itself, all types of hemoglobin.

1. Serine Protease Family

Serine proteases are classified as a family of related proteins. This is a family of enzymes that utilize a uniquely activated serine residue located in the active site for the binding and catalytic Hydrolysis of peptide bonds in protein substrates. The targets for serine proteases are specific peptide bonds in proteins (often in other serine proteases).

All proteins of this family are characterized by the presence of Ser₁₉₅, His₅₇, and Asp₁₀₂ residues in the active center (this numbering is used regardless of their exact position in the primary structure of a particular serine protease). A high degree of similarity in their three-dimensional structures has also been revealed, despite the fact that they contain identical amino acids at only 40% of their positions (Fig. 1-44). The catalytic region of serine proteases is located in a cleft between two domains.

Fig. 1-44. Three-dimensional structures of Elastase (A) and Chymotrypsin (B).

Certain amino acid substitutions have led to Changes in the substrate specificity of these proteins and to the emergence of functional diversity within this family. Thus, digestive serine proteases participate in the Digestion (hydrolytic Cleavage of peptide bonds) of denatured dietary proteins. These include trypsin, chymotrypsin, and elastase, though each of these enzymes prefers to cleave peptide bonds formed by specific amino acids.

Serine proteases involved in strictly controlled physiological processes—such as the activation of the blood clotting protein cascade, Fibrinolysis, the activation of complement system proteins, and the generation of protein hormones—possess an even greater substrate specificity. During the activation of native proteins, serine proteases hydrolyze one or two specific peptide bonds out of the hundreds present in the protein substrate. This is because, in the native protein, the enzyme recognizes not only the amino acids directly forming the peptide bond, but also certain amino acid residues surrounding the bond undergoing Enzymatic hydrolysis.

More detailed information on serine proteases can be found in Sections 9 and 14.

2. Immunoglobulin Superfamily

Proteins belonging to the immunoglobulin superfamily play a tremendous role in the functioning of the immune system. This superfamily includes at least three major families of proteins involved in the body's immune defense: the immunoglobulin family, the family of T-cell antigen-recognizing receptors, and class I and II Major Histocompatibility Complex proteins, which are referred to in literature as MHC. The superfamily also includes the family of adhesion proteins involved in the recognition of specific cell types and their intercellular interactions.

The primary criterion for including proteins in the immunoglobulin superfamily is their domain Organization, along with significant homology in amino acid sequences and the three-dimensional structures of individual domains. Furthermore, the proteins of this superfamily share similar functions: immunoglobulins interact with foreign structures present in the blood, lymph, intercellular fluid, or glandular secretions, whereas T-lymphocyte receptors and major histocompatibility complex proteins interact with Antigens located On the surface of the organism's own cells.

3. Immunoglobulin Family

Immunoglobulins, or Antibodies, are specific proteins produced by B-lymphocytes in response to The entry of foreign structures known as antigens into the body. The human body produces about 10⁷ clones of B-lymphocytes, each specialized in producing one of 10⁷ types of immunoglobulins.

All immunoglobulins are characterized by a common structural plan, which we will examine using the structure of IgG as an example.

An IgG molecule consists of four polypeptide chains: two identical light chains (L, from light), containing about 220 amino acid residues, and two heavy chains (H, from heavy), consisting of 440 amino acids each. All 4 chains are connected to each other by numerous non-covalent bonds and four Disulfide Bonds. Therefore, the IgG molecule is classified as a monomer.

IgG light chains consist of 2 domains: a variable domain (V_L) located in the N-terminal region of the polypeptide chain, and a constant domain (C_L) located at the C-terminus. Each domain consists of 2 layers with a β-sheet structure, where the segments of the polypeptide chain lie antiparallel. The β-sheets are covalently linked by a disulfide bond approximately in the middle of the domain (Fig. 1-45).

Fig. 1-45. Structure of immunoglobulin G.

IgG heavy chains have 4 domains: one variable domain (V_H) located at the N-terminus, and three constant domains (C_H1, C_H2, C_H3). The domains of IgG heavy chains share a homologous structure with the domains of light chains. Between the two constant domains of the heavy chains, C_H1 and C_H2, There is a region containing a high number of proline residues that hinder the Formation of secondary structure and the interaction of neighboring H-chains in this segment. This region is called the "hinge region"; it imparts flexibility to the molecule.

Located between the variable domains of the heavy and light chains are two identical sites that bind two identical specific antigens; therefore, such antibodies are often referred to as "bivalent." Antigen-antibody binding does not involve the entire amino acid sequence of the variable domains of both chains, but rather a mere 20–30 amino acids located in the hypervariable regions of each chain. It is these regions that determine The unique ability of each antibody clone to interact with its corresponding (complementary) antigen.

The primary functions of antibodies are the detection and binding of foreign antigens located outside the body's cells (in the blood, lymph, intercellular fluid, and mucosal secretions). This occurs via specific antigen-binding sites of various immunoglobulin clones. Moreover, the binding of antigen to antibody facilitates the subsequent destruction of foreign substances. The Specificity of the pathway leading to the destruction of the antigen-antibody complex depends on the antibody class.

Classes of immunoglobulins. There are 5 classes of immunoglobulin heavy chains, differing in the structure of their constant domains: α, δ, ε, γ, and μ. Accordingly, 5 classes of immunoglobulins are distinguished: A, D, E, G, and M. The structural Features of the heavy chains impart a conformation characteristic of each class to their hinge regions and C-terminal areas. The binding of an antigen to an antibody alters the conformation of the HEAVY CHAIN CONSTANT domains, which determines The pathway of complex degradation in the body (binding to complement system proteins or uptake by phagocytic cells).

Immunoglobulins M are the first class of antibodies synthesized in developing B-lymphocytes. There are 2 forms of immunoglobulins M: a monomeric, membrane-bound form and a pentameric form secreted by B-lymphocytes into the blood.

Membrane-bound form of immunoglobulins M. Maturing B lymphocytes synthesize monomeric bivalent IgM molecules structurally similar to the IgG molecules discussed above, which embed into The Plasma Membrane of cells to act as primary antigen-recognition receptors. The attachment of IgM to the membrane is mediated by a hydrophobic region located in the C-terminal ("tail") domain of the heavy chains, which contains 25 hydrophobic amino acid residues.

The interaction of an antigen with a receptor on The surface of a B lymphocyte triggers its proliferation and the formation of an entire clone of lymphocytes originating from a single antigen-stimulated cell. This clone of B lymphocytes will produce immunoglobulins with identical antigen-binding sites. However, B lymphocytes are capable of class switching to produce other classes of antibodies.

Secretory form of immunoglobulins M. When B lymphocytes first encounter a novel antigen in Body Fluids, they synthesize and secrete into the bloodstream IgM molecules consisting of five monomeric subunits linked together by disulfide bonds and an additional polypeptide J-chain (Fig. 1-46).

Fig. 1-46. Structure of the pentameric secretory immunoglobulin M molecule.

The heavy chains of their monomers lack the hydrophobic "tail" region. The pentameric molecule contains 10 antigen-binding sites, which increases the likelihood of binding a previously unknown antigen to the immunoglobulin (Fig. 1-47).

Fig. 1-47. Binding of IgM to bacterial cell antigens and their destruction by activated complement proteins.

The interaction of an antigen with IgM induces a conformational change that promotes the binding of its "tail" region to the first component of The Complement System. If the antigen is located on the surface of a microorganism, complement activation leads to the disruption of the cell membrane integrity and the destruction of the bacterial cell.

Immunoglobulins G. Quantitatively, IgG is the predominant immunoglobulin class in the blood, accounting for approximately 75% of total Serum proteins. The structure of IgG has been described in detail above. In the blood, IgG is found exclusively in monomeric form and is secreted by activated B lymphocytes in large quantities during the secondary Immune Response upon re-exposure to an antigen.

Four IgG subclasses have been identified in humans: IgGg₁, IgGg₂, IgGg₃, IgGg₄. The numerical suffix reflects the relative abundance of each subclass in serum (with IgGg₁ being the most abundant and IgGg₄ the least). The degree of sequence homology among these subclasses is very high (approximately 90–95%).

IgG not only efficiently binds and neutralizes foreign molecules and cells entering the body, but also facilitates their subsequent elimination. Conformational Changes in the "tail" region of IgG following antigen binding lead to the recruitment and activation of complement proteins. Furthermore, the C-terminal region of IgG can interact with specific receptors on macrophages and neutrophils, triggering the phagocytosis of antigen-antibody complexes and their degradation within phagosomes (Fig. 1-48).

Fig. 1-48. Phagocytosis of an antigen-antibody complex by a neutrophil. A – interaction of an IgG-coated bacterium with neutrophil receptors; B – engulfment of the bacterium by the neutrophil; C – digestion of the bacterium within the neutrophil phagosome.

IgG is the only antibody class capable of crossing the placental barrier, thereby providing intrauterine protection for the fetus against infections.

Immunoglobulins A. IgA is the principal antibody class present in bodily secretions (saliva, milk, digestive juices, and respiratory tract secretions). In blood serum, its concentration does not exceed 10–15% of the total immunoglobulins. Its monomeric form resembles IgG in structure. However, in secretions, IgA predominantly exists as a dimer, in which the monomers are joined by an additional J-peptide chain (Fig. 1-49).

Fig. 1-49. Structure of the dimeric immunoglobulin A molecule.

At the basal surface of epithelial cells, the IgA dimer specifically binds to cell-surface proteins known as the secretory component. The resulting complex is internalized via endocytosis and transported to the apical region. Here, the complex is cleaved by Proteolytic Enzymes, releasing the free dimer into the extracellular space (Fig. 1-50).

Fig. 1-50. Transport of immunoglobulins A across epithelial cells into glandular ducts.

The complex formed by the interaction of IgA with an antigen does not activate the complement system or phagocytic cells, but it prevents antigens from attaching to the epithelial cell surface and penetrating the body.

Immunoglobulins E. The concentration of this immunoglobulin class in the blood is extremely low. IgE molecules are monomers, but unlike IgG, their heavy chains contain four constant domains instead of three. Following Synthesis and Secretion into the bloodstream by B lymphocytes, IgE molecules bind via their C-terminal regions to specific receptors on the surface of mast cells and basophils, thereby functioning as cell-surface antigen receptors (Fig. 1-51).

Fig. 1-51. Release of BIOLOGICALLY ACTIVE SUBSTANCES by a mast cell triggered by antigen binding to surface-fixed IgE.

Once an antigen binds to at least two antigen-binding sites on two neighboring IgE molecules, the cell receives a signal to secrete biologically active substances (such as serotonin and histamine) stored in secretory vesicles. The release of these substances is largely responsible for the inflammatory response, as well as allergic reactions such as Bronchial Asthma, urticaria, and hay fever. Elevated IgE levels can precede the onset of allergic reactions.

Immunoglobulin D. IgD is found in the blood in very small amounts. These monomeric proteins act as receptors for B lymphocytes; no other functions for IgD have been identified to date.

4. The T-Cell Antigen-Recognizing Receptor Family

While antibodies produced by B lymphocytes bind to antigens in body fluids (mediating humoral Immunity), T lymphocytes interact with antigens on the surface of virus-infected cells and the body's own cells altered by tumor transformation (cell-mediated immunity). T lymphocytes recognize antigens only when presented in a complex with class I or class II MHC molecules, which are also present on the cell surface.

T-lymphocyte receptors — are heterodimers, meaning they consist of α and β chains. Each chain contains two immunoglobulin-like domains: a variable (V) domain and a constant (C) domain (Fig. 1-52). The C-terminal regions of each chain are embedded in the plasma membrane. A single antigen-binding site is located between the two variable domains, Vα and Vβ. The repertoire of T-cell receptors with distinct antigen-binding sites is comparable in diversity to immunoglobulins.

Fig. 1-52. Structure of the T-lymphocyte receptor.

Major Histocompatibility Complex Protein Family

Major histocompatibility complex proteins were discovered during studies on intraspecies tissue transplantation, which gave rise to their name. They are also referred to as MHC proteins (see above) or HLA proteins (human leukocyte antigens), as they were first discovered on human leukocytes.

There are two main classes of MHC molecules: class I and class II. Class I MHC molecules are found on the surface of virtually all human body cells, whereas class II MHC proteins are restricted to specific Cells of the immune system known as antigen-presenting cells. These primarily include macrophages and B lymphocytes that have encountered an antigen.

Class I MHC molecules — are heterodimers. They consist of a single polypeptide α chain non-covalently associated with a small extracellular protein, β₂-microglobulin. The polypeptide α chain comprises three extracellular globular domains (α₁, α₂, α₃), a transmembrane segment, and a carboxy-terminal tail located in the cytoplasm (Fig. 1-53, A). The α₃ domain and β₂-microglobulin share a conformation resembling the structure of immunoglobulins. The α₁ and α₂ domains contain variable regions capable of binding an "extended" antigen (most commonly a peptide fragment of a foreign protein) displayed on the cell surface.

Fig. 1-53. Structure of major histocompatibility complex proteins: class I MHC (A) and class II MHC (B).

Class II MHC molecules — are also heterodimers. They consist of two polypeptide chains, α and β, each featuring one conserved immunoglobulin-like domain and one variable domain at their N-terminal regions. Antigen binding occurs within the region of the variable domains of both the α and β chains (Fig. 1-53, B).

Foreign proteins within human cells (such as viral particle proteins) undergo Limited proteolysis in Lysosomes, and small fragments of these proteins are displayed on the cell membrane surface in association with class I or class II MHC proteins.

Peptide–MHC Protein Complexes are recognized by T-lymphocyte receptors. This results in a specific interaction (Fig. 1-54), activation of the T lymphocyte, and The Development of an immune response. For example, the Interaction of a cytotoxic T lymphocyte with the antigen–class I MHC complex on the surface of a virus-infected cell triggers the lymphocyte to release specialized proteins that cause damage and destruction of the infected cell.

Fig. 1-54. Specific interaction between a cytotoxic T-lymphocyte receptor and the antigen-MHC class I protein complex.

E. Isofunctional Proteins

Isofunctional proteins — are families of proteins that perform nearly identical or very similar functions, although subtle structural and functional differences among certain members of the family can hold significant physiological importance. Examples of such proteins include the human hemoglobin isoforms: HbA, HbA2, HbF, and others discussed previously. All of them are tetramers, yet they are composed of different sets of protomers (α, β, γ, δ). Hemoglobins perform the same function—binding O₂ and transporting it to tissues. However, each possesses unique functional properties. For instance, fetal hemoglobin (HbF) has a higher affinity for O₂ than HbA, which facilitates the diffusion of O₂ from maternal HbA in the blood to HbF in the fetal blood.

Iso-proteins — are Multiple Forms of a protein found within organisms of the same species. Proteins that perform identical functions in organisms of different biological species are termed "homologous proteins." For example, cytochrome c, a mitochondrial protein involved in Biological Oxidation, is present in many animal species. The Cytochromes c of chicken and duck differ by only two amino acid residues in their primary structure; they perform the same function, but because they belong to different species, they are classified as homologous proteins.

Iso-proteins also include numerous isoforms of the structural protein collagen (see Section 15). Many enzymes exist in multiple isoforms and are known as isozymes (see Section 2).