If You Were To Draw An Antibody, How Might You Sketch Out Its Basic Shape?
Vertebrates inevitably dice of infection if they are unable to make antibodies. Antibodies defend us against infection by bounden to viruses and microbial toxins, thereby inactivating them (run into Effigy 24-2). The binding of antibodies to invading pathogens also recruits various types of white blood cells and a organisation of blood proteins, collectively called complement (discussed in Chapter 25). The white blood cells and activated complement components work together to attack the invaders.
Synthesized exclusively by B cells, antibodies are produced in billions of forms, each with a unlike amino acrid sequence and a unlike antigen-bounden site. Collectively called immunoglobulins (abbreviated every bit Ig), they are among the most abundant protein components in the blood, constituting about twenty% of the total protein in plasma by weight. Mammals make v classes of antibodies, each of which mediates a characteristic biological response post-obit antigen binding. In this section, we hash out the structure and function of antibodies and how they interact with antigen.
B Cells Brand Antibodies as Both Prison cell-Surface Receptors and Secreted Molecules
As predicted past the clonal pick theory, all antibiotic molecules made by an private B cell have the same antigen-bounden site. The first antibodies made by a newly formed B cell are not secreted. Instead, they are inserted into the plasma membrane, where they serve as receptors for antigen. Each B cell has approximately 10v such receptors in its plasma membrane. As we talk over later, each of these receptors is stably associated with a complex of transmembrane proteins that activate intracellular signaling pathways when antigen binds to the receptor.
Each B cell produces a single species of antibiotic, each with a unique antigen-binding site. When a naïve or retentiveness B prison cell is activated past antigen (with the aid of a helper T cell), information technology proliferates and differentiates into an antibody-secreting effector cell. Such cells make and secrete large amounts of soluble (rather than membrane-jump) antibody, which has the aforementioned unique antigen-bounden site as the cell-surface antibody that served before as the antigen receptor (Figure 24-17). Effector B cells tin can begin secreting antibody while they are still small-scale lymphocytes, but the end stage of their maturation pathway is a large plasma jail cell (run into Figure 24-7B), which continuously secretes antibodies at the astonishing rate of about 2000 molecules per second. Plasma cells seem to accept committed and then much of their poly peptide-synthesizing machinery to making antibody that they are incapable of further growth and partition. Although many die later several days, some survive in the bone marrow for months or years and continue to secrete antibodies into the blood.
Figure 24-17
B prison cell activation. When naïve or memory B cells are activated by antigen (and helper T cells—not shown), they proliferate and differentiate into effector cells. The effector cells produce and secrete antibodies with a unique antigen-bounden (more than...)
A Typical Antibody Has 2 Identical Antigen-Binding Sites
The simplest antibodies are Y-shaped molecules with two identical antigen-bounden sites, one at the tip of each arm of the Y (Figure 24-xviii). Considering of their two antigen-binding sites, they are described as bivalent. As long as an antigen has three or more antigenic determinants, bivalent antibody molecules can cross-link it into a large lattice (Effigy 24-nineteen). This lattice tin can be rapidly phagocytosed and degraded by macrophages. The efficiency of antigen binding and cross-linking is greatly increased by a flexible hinge region in most antibodies, which allows the distance between the two antigen-bounden sites to vary (Figure 24-twenty).
Effigy 24-18
A uncomplicated representation of an antibody molecule. Note that its two antigen-binding sites are identical.
Figure 24-19
Antibody-antigen interactions. Because antibodies take two identical antigen-bounden sites, they can cantankerous-link antigens. The types of antibiotic-antigen complexes that course depend on the number of antigenic determinants on the antigen. Here a single species (more...)
Figure 24-twenty
The hinge region of an antibody molecule. Because of its flexibility, the swivel region improves the efficiency of antigen binding and cross-linking.
The protective effect of antibodies is non due simply to their ability to bind antigen. They engage in a variety of activities that are mediated by the tail of the Y-shaped molecule. Every bit we hash out later, antibodies with the aforementioned antigen-binding sites can have any ane of several different tail regions. Each type of tail region gives the antibody different functional backdrop, such equally the ability to activate the complement arrangement, to bind to phagocytic cells, or to cross the placenta from mother to fetus.
An Antibody Molecule Is Composed of Heavy and Calorie-free Chains
The basic structural unit of an antibody molecule consists of four polypeptide bondage, two identical light (L) chains (each containing about 220 amino acids) and ii identical heavy (H) chains (each commonly containing about 440 amino acids). The four chains are held together by a combination of noncovalent and covalent (disulfide) bonds. The molecule is equanimous of two identical halves, each with the same antigen-binding site. Both calorie-free and heavy chains usually cooperate to form the antigen-binding surface (Figure 24-21).
Effigy 24-21
A schematic drawing of a typical antibody molecule. Information technology is composed of four polypeptide chains—2 identical heavy chains and two identical lite chains. The 2 antigen-binding sites are identical, each formed by the Due north-terminal region of a low-cal (more than...)
There Are Five Classes of Heavy Chains, Each With Unlike Biological Properties
In mammals, there are five classes of antibodies, IgA, IgD, IgE, IgG, and IgM, each with its own grade of heavy chain—α, δ, ε, γ, and μ, respectively. IgA molecules have α bondage, IgG molecules have γ chains, and and then on. In add-on, in that location are a number of subclasses of IgG and IgA immunoglobulins; for example, there are 4 human IgG subclasses (IgG1, IgG2, IgG3, and IgG4), having γi, γ2, γiii, andγ4 heavy chains, respectively. The various heavy chains give a distinctive conformation to the hinge and tail regions of antibodies, so that each class (and bracket) has feature properties of its ain.
IgM, which has μ heavy chains, is ever the beginning form of antibiotic made past a developing B prison cell, although many B cells eventually switch to making other classes of antibody (discussed below). The immediate precursor of a B jail cell, called a pre-B cell, initially makes μ chains, which associate with so-chosen surrogate lite chains (substituting for 18-carat light bondage) and insert into the plasma membrane. The complexes of μ chains and surrogate light bondage are required for the cell to progress to the next stage of development, where it makes bona fide light bondage. The light chains combine with the μ bondage, replacing the surrogate light chains, to grade four-concatenation IgM molecules (each with two μ chains and two light chains). These molecules then insert into the plasma membrane, where they part every bit receptors for antigen. At this point, the cell is called an immature naïve B cell. Later on leaving the bone marrow, the cell starts to produce cell-surface IgD molecules as well, with the same antigen-binding site as the IgM molecules. It is at present called a mature naïve B cell. It is this prison cell that tin respond to foreign antigen in peripheral lymphoid organs (Figure 24-22).
Effigy 24-22
The primary stages in B cell evolution. All of the stages shown occur independently of antigen. When they are activated by their specific foreign antigen and helper T cells in peripheral lymphoid organs, mature naïve B cells proliferate and differentiate (more...)
IgM is not simply the first course of antibody to appear on the surface of a developing B cell. It is also the major class secreted into the claret in the early stages of a main antibody response, on kickoff exposure to an antigen. (Dissimilar IgM, IgD molecules are secreted in only small amounts and seem to function mainly as prison cell-surface receptors for antigen.) In its secreted class, IgM is a pentamer composed of five 4-chain units, giving information technology a full of ten antigen-bounden sites. Each pentamer contains 1 copy of another polypeptide chain, chosen a J (joining) concatenation. The J chain is produced by IgM-secreting cells and is covalently inserted between two adjacent tail regions (Figure 24-23).
Figure 24-23
A pentameric IgM molecule. The five subunits are held together by disulfide bonds (red). A single J chain, which has a structure like to that of a single Ig domain (discussed later), is disulfide-bonded between the tails of two μ heavy bondage. (more...)
The binding of an antigen to a single secreted pentameric IgM molecule tin activate the complement system. As discussed in Affiliate 25, when the antigen is on the surface of an invading pathogen, this activation of complement can either mark the pathogen for phagocytosis or kill it direct.
The major class of immunoglobulin in the blood is IgG, which is a iv-chain monomer produced in large quantities during secondary allowed responses. Besides activating complement, the tail region of an IgG molecule binds to specific receptors on macrophages and neutrophils. Largely by means of such Fc receptors (so-named because antibody tails are chosen Fc regions), these phagocytic cells bind, ingest, and destroy infecting microorganisms that have get coated with the IgG antibodies produced in response to the infection (Effigy 24-24).
Effigy 24-24
Antibiotic-activated phagocytosis. (A) An IgG-antibody-coated bacterium is efficiently phagocytosed by a macrophage or neutrophil, which has cell-surface receptors that bind the tail (Fc) region of IgG molecules. The binding of the antibody-coated bacterium (more...)
IgG molecules are the merely antibodies that tin can pass from mother to fetus via the placenta. Cells of the placenta that are in contact with maternal blood have Fc receptors that bind blood-borne IgG molecules and direct their passage to the fetus. The antibody molecules bound to the receptors are start taken into the placental cells past receptor-mediated endocytosis. They are so transported across the cell in vesicles and released by exocytosis into the fetal blood (a process chosen transcytosis, discussed in Affiliate xiii). Considering other classes of antibodies practise non bind to these particular Fc receptors, they cannot pass across the placenta. IgG is also secreted into the mother's milk and is taken up from the gut of the neonate into the claret, providing protection for the baby against infection.
IgA is the principal class of antibody in secretions, including saliva, tears, milk, and respiratory and intestinal secretions. Whereas IgA is a four-chain monomer in the blood, information technology is an 8-chain dimer in secretions (Effigy 24-25). It is transported through secretory epithelial cells from the extracellular fluid into the secreted fluid by another type of Fc receptor that is unique to secretory epithelia (Figure 24-26). This Fc receptor can as well ship IgM into secretions (but less efficiently), which is probably why individuals with a selective IgA deficiency, the most common form of antibody deficiency, are just mildly affected by the defect.
Figure 24-25
A highly schematized diagram of a dimeric IgA molecule constitute in secretions. In add-on to the two IgA monomers, there is a unmarried J chain and an additional polypeptide chain called the secretory component, which is idea to protect the IgA molecules (more...)
Figure 24-26
The mechanism of transport of a dimeric IgA molecule beyond an epithelial prison cell. The IgA molecule, as a J-chain-containing dimer, binds to a transmembrane receptor poly peptide on the nonlumenal surface of a secretory epithelial cell. The receptor-IgA complexes (more...)
The tail region of IgE molecules, which are 4-chain monomers, binds with unusually high affinity (K a ~ 1010 liters/mole) to yet another form of Fc receptors. These receptors are located on the surface of mast cells in tissues and of basophils in the claret. The IgE molecules bound to them function as passively acquired receptors for antigen. Antigen bounden triggers the mast jail cell or basophil to secrete a multifariousness of cytokines and biologically agile amines, especially histamine (Figure 24-27). These molecules crusade blood vessels to dilate and become leaky, which in plow helps white blood cells, antibodies, and complement components to enter sites of infection. The same molecules are also largely responsible for the symptoms of such allergic reactions equally hay fever, asthma, and hives. In improver, mast cells secrete factors that concenter and activate white claret cells called eosinophils. These cells also have Fc receptors that bind IgE molecules and can kill various types of parasites, particularly if the parasites are coated with IgE antibodies.
Figure 24-27
The role of IgE in histamine secretion by mast cells. A mast cell (or a basophil) binds IgE molecules after they are secreted by activated B cells. The soluble IgE antibodies bind to Fc receptor proteins on the mast cell surface that specifically recognize (more than...)
In addition to the five classes of heavy bondage found in antibody molecules, higher vertebrates have two types of light chains, κ and λ, which seem to be functionally indistinguishable. Either blazon of light chain may be associated with any of the heavy chains. An individual antibody molecule, however, e'er contains identical light chains and identical heavy chains: an IgG molecule, for example, may have either κ or λ light chains, simply not ane of each. As a result of this symmetry, an antibody's antigen-binding sites are always identical. Such symmetry is crucial for the cantankerous-linking function of secreted antibodies (run across Figure 24-19).
The properties of the various classes of antibodies in humans are summarized in Table 24-1.
Table 24-1
Backdrop of the Major Classes of Antibodies in Humans.
The Strength of an Antibody-Antigen Interaction Depends on Both the Number and the Affinity of the Antigen-Binding Sites
The binding of an antigen to antibody, like the bounden of a substrate to an enzyme, is reversible. It is mediated by the sum of many relatively weak non-covalent forces, including hydrogen bonds and hydrophobic van der Waals forces, and ionic interactions. These weak forces are effective simply when the antigen molecule is shut plenty to let some of its atoms to fit into complementary recesses on the surface of the antibody. The complementary regions of a four-chain antibiotic unit are its 2 identical antigen-binding sites; the corresponding region on the antigen is an antigenic determinant (Effigy 24-28). Most antigenic macromolecules accept many different antigenic determinants and are said to exist multivalent; if two or more of them are identical (as in a polymer with a repeating structure), the antigen is said to exist polyvalent (Figure 24-29).
Figure 24-28
Antigen bounden to antibiotic. In this highly schematized diagram, an antigenic determinant on a macromolecule is shown interacting with the antigen-bounden site of 2 different antibody molecules, one of high affinity and ane of low affinity. The antigenic (more...)
Figure 24-29
Molecules with multiple antigenic determinants. (A) A globular protein is shown with a number of dissimilar antigenic determinants. Unlike regions of a polypeptide chain usually come together in the folded structure to form each antigenic determinant (more...)
The reversible binding reaction between an antigen with a unmarried antigenic determinant (denoted Ag) and a single antigen-binding site (denoted Ab) tin can be expressed as
The equilibrium bespeak depends both on the concentrations of Ab and Ag and on the forcefulness of their interaction. Clearly, a larger fraction of Ab will go associated with Ag as the concentration of Ag increases. The strength of the interaction is generally expressed as the affinity constant ( K a ) (see Figure 3-44), where
(the square brackets signal the concentration of each component at equilibrium).
The affinity constant, sometimes chosen the association abiding, tin exist adamant past measuring the concentration of costless Ag required to fill half of the antigen-binding sites on the antibody. When half the sites are filled, [AgAb] = [Ab] and One thousand a = 1/[Ag]. Thus, the reciprocal of the antigen concentration that produces half the maximum binding is equal to the affinity constant of the antibody for the antigen. Common values range from equally depression as 5 × ten4 to as high as 1011 liters/mole.
The affinity of an antibiotic for an antigenic determinant describes the strength of binding of a unmarried copy of the antigenic determinant to a single antigen-bounden site, and it is independent of the number of sites. When, however, a polyvalent antigen, conveying multiple copies of the same antigenic determinant, combines with a polyvalent antibody, the binding strength is greatly increased considering all of the antigen-antibody bonds must be broken simultaneously before the antigen and antibody can dissociate. As a result, a typical IgG molecule tin bind at to the lowest degree 100 times more strongly to a polyvalent antigen if both antigen-binding sites are engaged than if but ane site is engaged. The total binding strength of a polyvalent antibody with a polyvalent antigen is referred to as the avidity of the interaction.
If the affinity of the antigen-bounden sites in an IgG and an IgM molecule is the same, the IgM molecule (with 10 binding sites) will have a much greater avidity for a multivalent antigen than an IgG molecule (which has 2 binding sites). This difference in avidity, often 104-fold or more, is important because antibodies produced early in an immune response commonly have much lower affinities than those produced after. Because of its high full avidity, IgM—the major Ig course produced early in immune responses—tin can office effectively fifty-fifty when each of its binding sites has just a low affinity.
So far we have considered the full general construction and function of antibodies. Next nosotros look at the details of their structure, as revealed by studies of their amino acrid sequence and three-dimensional construction.
Light and Heavy Chains Consist of Constant and Variable Regions
Comparison of the amino acid sequences of different antibody molecules reveals a striking feature with important genetic implications. Both calorie-free and heavy chains have a variable sequence at their North-concluding ends just a constant sequence at their C-terminal ends. Consequently, when the amino acrid sequences of many different κ chains are compared, the C-last halves are the same or bear witness only minor differences, whereas the N-terminal halves are all very unlike. Low-cal chains have a abiding region about 110 amino acids long and a variable region of the same size. The variable region of the heavy chains (at their North-terminus) is also about 110 amino acids long, but the heavy-chain abiding region is about 3 or four times longer (330 or 440 amino acids), depending on the class (Figure 24-30).
Figure 24-30
Abiding and variable regions of immunoglobulin bondage. Both light and heavy chains of an antibiotic molecule take singled-out abiding and variable regions.
It is the Northward-terminal ends of the light and heavy bondage that come together to course the antigen-binding site (see Effigy 24-21), and the variability of their amino acid sequences provides the structural ground for the diversity of antigen-binding sites. The diverseness in the variable regions of both light and heavy bondage is for the nearly function restricted to three small hypervariable regions in each chain; the remaining parts of the variable region, known as framework regions, are relatively constant. Only the v–x amino acids in each hypervariable region form the antigen-binding site (Effigy 24-31). As a event, the size of the antigenic determinant that an antibody recognizes is mostly comparably small. It can consist of fewer than 25 amino acids on the surface of a globular protein, for example.
Figure 24-31
Antibody hypervariable regions. Highly schematized drawing of how the three hypervariable regions in each lite and heavy chain together form the antigen-binding site of an antibody molecule.
The Lite and Heavy Chains Are Composed of Repeating Ig Domains
Both light and heavy bondage are fabricated up of repeating segments—each about 110 amino acids long and each containing 1 intrachain disulfide bond. These repeating segments fold independently to grade compact functional units chosen immunoglobulin (Ig) domains. As shown in Figure 24-32, a calorie-free chain consists of i variable (V50) and one abiding (C50) domain (equivalent to the variable and constant regions shown in the top half of Effigy 24-30). These domains pair with the variable (FiveH) and first constant (CH1) domain of the heavy chain to form the antigen-binding region. The remaining constant domains of the heavy chains grade the Fc region, which determines the other biological properties of the antibody. Most heavy chains have three constant domains (CH1, CH2, and CH3), merely those of IgM and IgE antibodies have 4.
Figure 24-32
Immunoglobulin domains. The light and heavy chains in an antibiotic molecule are each folded into repeating domains that are similar to one another. The variable domains (shaded in blue) of the low-cal and heavy chains (5L and VH) make up the antigen-bounden (more...)
The similarity in their domains suggests that antibody bondage arose during development by a series of factor duplications, get-go with a primordial gene coding for a single 110 amino acid domain of unknown function. This hypothesis is supported past the finding that each domain of the constant region of a heavy chain is encoded by a separate coding sequence (exon) (Effigy 24-33).
Figure 24-33
The organization of the Deoxyribonucleic acid sequences that encode the constant region of an antibiotic heavy concatenation. The coding sequences (exons) for each domain and for the swivel region are separated by noncoding sequences (introns). The intron sequences are removed past (more than...)
An Antigen-Binding Site Is Constructed From Hypervariable Loops
A number of fragments of antibodies, likewise as intact antibody molecules, accept been studied by 10-ray crystallography. From these examples, nosotros can understand the way in which billions of unlike antigen-binding sites are constructed on a mutual structural theme.
As illustrated in Figure 24-34, each Ig domain has a very like iii-dimensional construction based on what is called the immunoglobulin fold, which consists of a sandwich of ii β sheets held together by a disulfide bond. We shall see later that many other proteins on the surface of lymphocytes and other cells, many of which function equally cell-cell adhesion molecules (discussed in Chapter 19), contain similar domains and hence are members of a very large immunoglobulin (Ig) superfamily of proteins.
Effigy 24-34
The folded structure of an IgG antibody molecule, based on x-ray crystallography studies. The construction of the whole protein is shown in the middle, while the construction of a constant domain is shown on the left and of a variable domain on the correct. Both (more...)
The variable domains of antibody molecules are unique in that each has its detail set of 3 hypervariable regions, which are bundled in three hypervariable loops (see Effigy 24-34). The hypervariable loops of both the light and heavy variable domains are amassed together to class the antigen-bounden site. Because the variable region of an antibody molecule consists of a highly conserved rigid framework, with hypervariable loops attached at ane stop, an enormous diversity of antigen-binding sites can be generated by changing only the lengths and amino acid sequences of the hypervariable loops. The overall 3-dimensional structure necessary for antibody part remains constant.
X-ray analyses of crystals of antibody fragments bound to an antigenic determinant reveal exactly how the hypervariable loops of the lite and heavy variable domains cooperate to form an antigen-binding surface in particular cases. The dimensions and shape of each different site vary depending on the conformations of the polypeptide chain in the hypervariable loops, which in turn are determined past the sequences of the amino acid side bondage in the loops. The shapes of bounden sites vary greatly—from pockets, to grooves, to undulating flatter surfaces, and even to protrusions—depending on the antibody (Figure 24-35). Smaller ligands tend to bind to deeper pockets, whereas larger ones tend to bind to flatter surfaces. In addition, the binding site can alter its shape after antigen bounden to improve fit the ligand.
Figure 24-35
Antigen-bounden sites of antibodies. The hypervariable loops of dissimilar 5L and 5H domains tin can combine to class a big variety of binding surfaces. The antigenic determinants and the antigen-binding site of the antibodies are shown in red. Only one antigen-binding (more...)
Now that we have discussed the structure and functions of antibodies, we are set to consider the crucial question that puzzled immunologists for many years—what are the genetic mechanisms that enable each of us to make many billions of different antibody molecules?
Summary
Antibodies defend vertebrates against infection by inactivating viruses and microbial toxins and past recruiting the complement arrangement and various types of white blood cell to kill the invading pathogens. A typical antibody molecule is Y-shaped, with two identical antigen-binding sites at the tips of the Y and bounden sites for complement components and/or various cell-surface receptors on the tail of the Y.
Each B cell clone makes antibody molecules with a unique antigen-binding site. Initially, during B jail cell development in the os marrow, the antibody molecules are inserted into the plasma membrane, where they serve as receptors for antigen. In peripheral lymphoid organs, antigen binding to these receptors, together with costimulatory signals provided past helper T cells, activates the B cells to proliferate and differentiate into either memory cells or antibiotic-secreting effector cells. The effector cells secrete antibodies with the same unique antigen-binding site equally the membrane-bound antibodies.
A typical antibody molecule is equanimous of four polypeptide chains, two identical heavy chains and two identical calorie-free bondage. Parts of both the heavy and light chains usually combine to class the antigen-binding sites. There are v classes of antibodies (IgA, IgD, IgE, IgG, and IgM), each with a distinctive heavy chain (α, δ, ε, γ, and μ, respectively). The heavy chains also grade the tail (Fc region) of the antibiotic, which determines what other proteins volition bind to the antibody and therefore what biological properties the antibody class has. Either blazon of light concatenation (κ or λ) can be associated with whatever class of heavy concatenation, just the type of light chain does not seem to influence the backdrop of the antibody, other than its specificity for antigen.
Each calorie-free and heavy chain is equanimous of a number of Ig domains—β sail structures containing about 110 amino acids. A calorie-free chain has one variable (VL) and one abiding (CFifty) domain, while a heavy concatenation has one variable (VH) and three or 4 constant (CH) domains. The amino acid sequence variation in the variable domains of both light and heavy chains is mainly confined to several small hypervariable regions, which protrude as loops at one end of the domains to course the antigen-binding site.
Source: https://www.ncbi.nlm.nih.gov/books/NBK26884/
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