Drag the Images to Their Corresponding Class to Review the Structure and Function of Antibodies
Vertebrates inevitably die of infection if they are unable to make antibodies. Antibodies defend usa against infection by binding to viruses and microbial toxins, thereby inactivating them (encounter Figure 24-2). The binding of antibodies to invading pathogens too recruits various types of white blood cells and a system of blood proteins, collectively chosen complement (discussed in Chapter 25). The white blood cells and activated complement components work together to assail the invaders.
Synthesized exclusively by B cells, antibodies are produced in billions of forms, each with a unlike amino acid sequence and a unlike antigen-binding site. Collectively called immunoglobulins (abbreviated as Ig), they are among the nearly arable protein components in the blood, constituting near 20% of the total protein in plasma by weight. Mammals brand 5 classes of antibodies, each of which mediates a characteristic biological response post-obit antigen binding. In this section, nosotros discuss the structure and office of antibodies and how they interact with antigen.
B Cells Brand Antibodies every bit Both Prison cell-Surface Receptors and Secreted Molecules
As predicted past the clonal selection theory, all antibiotic molecules fabricated by an individual B cell have the same antigen-binding site. The first antibodies made past a newly formed B cell are non secreted. Instead, they are inserted into the plasma membrane, where they serve every bit receptors for antigen. Each B cell has approximately 10five such receptors in its plasma membrane. Equally 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 jail cell produces a unmarried species of antibody, each with a unique antigen-bounden site. When a naïve or memory B prison cell is activated past antigen (with the assist of a helper T cell), it proliferates and differentiates into an antibody-secreting effector prison cell. Such cells make and secrete large amounts of soluble (rather than membrane-spring) antibody, which has the same unique antigen-binding site as the prison cell-surface antibody that served earlier equally the antigen receptor (Figure 24-17). Effector B cells tin can begin secreting antibody while they are still small lymphocytes, only the end stage of their maturation pathway is a large plasma cell (run into Figure 24-7B), which continuously secretes antibodies at the astonishing rate of about 2000 molecules per second. Plasma cells seem to take committed so much of their protein-synthesizing machinery to making antibody that they are incapable of further growth and division. Although many dice later several days, some survive in the bone marrow for months or years and go on to secrete antibodies into the blood.
Figure 24-17
B 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-binding (more...)
A Typical Antibiotic Has Ii Identical Antigen-Bounden Sites
The simplest antibodies are Y-shaped molecules with two identical antigen-binding sites, ane at the tip of each arm of the Y (Figure 24-eighteen). Considering of their two antigen-binding sites, they are described equally bivalent. As long as an antigen has three or more antigenic determinants, bivalent antibody molecules can cross-link information technology into a large lattice (Figure 24-19). This lattice can be chop-chop phagocytosed and degraded by macrophages. The efficiency of antigen bounden and cross-linking is greatly increased by a flexible hinge region in most antibodies, which allows the distance betwixt the ii antigen-binding sites to vary (Figure 24-20).
Figure 24-18
A simple representation of an antibody molecule. Annotation that its 2 antigen-binding sites are identical.
Figure 24-nineteen
Antibody-antigen interactions. Because antibodies accept two identical antigen-bounden sites, they can cross-link antigens. The types of antibody-antigen complexes that form depend on the number of antigenic determinants on the antigen. Hither a single species (more...)
Figure 24-20
The hinge region of an antibody molecule. Because of its flexibility, the hinge region improves the efficiency of antigen binding and cross-linking.
The protective result of antibodies is not due simply to their power to bind antigen. They engage in a diverseness of activities that are mediated by the tail of the Y-shaped molecule. Every bit nosotros discuss later, antibodies with the same antigen-bounden sites can take any one of several different tail regions. Each type of tail region gives the antibody different functional backdrop, such as the ability to activate the complement organization, to bind to phagocytic cells, or to cross the placenta from female parent to fetus.
An Antibody Molecule Is Composed of Heavy and Calorie-free Chains
The basic structural unit of measurement of an antibiotic molecule consists of iv polypeptide bondage, two identical lite (L) bondage (each containing about 220 amino acids) and two identical heavy (H) chains (each usually containing nigh 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 light and heavy bondage commonly cooperate to grade the antigen-binding surface (Figure 24-21).
Effigy 24-21
A schematic cartoon of a typical antibody molecule. It is composed of four polypeptide chains—two identical heavy bondage and two identical calorie-free chains. The 2 antigen-bounden sites are identical, each formed by the Due north-concluding region of a light (more than...)
There Are Five Classes of Heavy Bondage, Each With Dissimilar Biological Properties
In mammals, in that location are five classes of antibodies, IgA, IgD, IgE, IgG, and IgM, each with its own grade of heavy concatenation—α, δ, ε, γ, and μ, respectively. IgA molecules have α chains, IgG molecules have γ bondage, and so on. In addition, at that place are a number of subclasses of IgG and IgA immunoglobulins; for instance, in that location are 4 man IgG subclasses (IgG1, IgG2, IgG3, and IgG4), having γ1, γtwo, γiii, andγiv heavy bondage, respectively. The various heavy chains give a distinctive conformation to the hinge and tail regions of antibodies, so that each class (and subclass) has feature properties of its own.
IgM, which has μ heavy chains, is always the first class of antibiotic fabricated past a developing B jail cell, although many B cells somewhen switch to making other classes of antibiotic (discussed below). The immediate precursor of a B prison cell, called a pre-B cell, initially makes μ chains, which associate with so-called surrogate low-cal chains (substituting for genuine light chains) and insert into the plasma membrane. The complexes of μ bondage and surrogate light chains are required for the prison cell to progress to the next phase of evolution, where it makes bona fide light chains. The light bondage combine with the μ chains, replacing the surrogate light bondage, to course four-chain IgM molecules (each with two μ chains and two light chains). These molecules then insert into the plasma membrane, where they role as receptors for antigen. At this signal, the cell is called an immature naïve B prison cell. After leaving the bone marrow, the jail cell starts to produce cell-surface IgD molecules equally well, with the same antigen-binding site as the IgM molecules. It is at present called a mature naïve B cell. Information technology is this cell that can respond to foreign antigen in peripheral lymphoid organs (Figure 24-22).
Figure 24-22
The chief stages in B cell development. 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 non only the first course of antibody to appear on the surface of a developing B cell. It is also the major class secreted into the blood in the early stages of a primary antibiotic response, on first exposure to an antigen. (Unlike IgM, IgD molecules are secreted in only small amounts and seem to function mainly as jail cell-surface receptors for antigen.) In its secreted grade, IgM is a pentamer equanimous of five four-chain units, giving it a full of 10 antigen-binding sites. Each pentamer contains one copy of some other polypeptide chain, called a J (joining) chain. The J chain is produced by IgM-secreting cells and is covalently inserted betwixt 2 adjacent tail regions (Effigy 24-23).
Figure 24-23
A pentameric IgM molecule. The five subunits are held together by disulfide bonds (cherry). A single J chain, which has a structure similar to that of a single Ig domain (discussed subsequently), is disulfide-bonded between the tails of two μ heavy chains. (more...)
The binding of an antigen to a single secreted pentameric IgM molecule can activate the complement organization. As discussed in Chapter 25, when the antigen is on the surface of an invading pathogen, this activation of complement tin either mark the pathogen for phagocytosis or kill it directly.
The major grade of immunoglobulin in the blood is IgG, which is a four-concatenation monomer produced in large quantities during secondary allowed responses. Too activating complement, the tail region of an IgG molecule binds to specific receptors on macrophages and neutrophils. Largely by ways of such Fc receptors (so-named because antibody tails are called Fc regions), these phagocytic cells bind, ingest, and destroy infecting microorganisms that have become coated with the IgG antibodies produced in response to the infection (Figure 24-24).
Figure 24-24
Antibiotic-activated phagocytosis. (A) An IgG-antibody-coated bacterium is efficiently phagocytosed past a macrophage or neutrophil, which has jail cell-surface receptors that demark the tail (Fc) region of IgG molecules. The binding of the antibody-coated bacterium (more...)
IgG molecules are the only antibodies that can pass from mother to fetus via the placenta. Cells of the placenta that are in contact with maternal claret have Fc receptors that bind blood-borne IgG molecules and straight their passage to the fetus. The antibiotic molecules spring to the receptors are first taken into the placental cells by receptor-mediated endocytosis. They are then transported beyond the cell in vesicles and released past exocytosis into the fetal blood (a process called transcytosis, discussed in Chapter 13). Because other classes of antibodies do non demark to these detail Fc receptors, they cannot pass across the placenta. IgG is as well secreted into the female parent'due south milk and is taken upward 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 claret, it is an eight-chain dimer in secretions (Figure 24-25). It is transported through secretory epithelial cells from the extracellular fluid into the secreted fluid past another blazon of Fc receptor that is unique to secretory epithelia (Effigy 24-26). This Fc receptor can too transport IgM into secretions (but less efficiently), which is probably why individuals with a selective IgA deficiency, the near common form of antibody deficiency, are only mildly affected by the defect.
Figure 24-25
A highly schematized diagram of a dimeric IgA molecule found in secretions. In addition to the two IgA monomers, there is a single J chain and an boosted polypeptide concatenation called the secretory component, which is thought to protect the IgA molecules (more...)
Effigy 24-26
The mechanism of transport of a dimeric IgA molecule across an epithelial cell. The IgA molecule, as a J-chain-containing dimer, binds to a transmembrane receptor protein on the nonlumenal surface of a secretory epithelial jail cell. The receptor-IgA complexes (more...)
The tail region of IgE molecules, which are four-chain monomers, binds with unusually high analogousness (K a ~ 1010 liters/mole) to yet another class of Fc receptors. These receptors are located on the surface of mast cells in tissues and of basophils in the blood. The IgE molecules spring to them role equally passively acquired receptors for antigen. Antigen binding triggers the mast prison cell or basophil to secrete a diverseness of cytokines and biologically agile amines, peculiarly histamine (Figure 24-27). These molecules cause claret vessels to dilate and go leaky, which in turn helps white blood cells, antibodies, and complement components to enter sites of infection. The same molecules are as well largely responsible for the symptoms of such allergic reactions every bit hay fever, asthma, and hives. In add-on, mast cells secrete factors that attract and activate white blood cells called eosinophils. These cells also accept Fc receptors that demark IgE molecules and can kill various types of parasites, especially if the parasites are coated with IgE antibodies.
Figure 24-27
The office of IgE in histamine secretion by mast cells. A mast prison 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 improver to the v classes of heavy chains constitute in antibiotic molecules, higher vertebrates have two types of light bondage, κ and λ, which seem to exist functionally duplicate. Either type of calorie-free chain may be associated with whatever of the heavy chains. An individual antibody molecule, however, always contains identical calorie-free chains and identical heavy chains: an IgG molecule, for instance, may take either κ or λ light chains, merely not ane of each. Equally a event of this symmetry, an antibody's antigen-binding sites are always identical. Such symmetry is crucial for the cross-linking role of secreted antibodies (see Figure 24-19).
The properties of the various classes of antibodies in humans are summarized in Table 24-ane.
Table 24-1
Properties of the Major Classes of Antibodies in Humans.
The Force of an Antibiotic-Antigen Interaction Depends on Both the Number and the Affinity of the Antigen-Binding Sites
The binding of an antigen to antibiotic, like the binding 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 merely when the antigen molecule is close enough to permit some of its atoms to fit into complementary recesses on the surface of the antibody. The complementary regions of a 4-chain antibody unit are its 2 identical antigen-bounden sites; the corresponding region on the antigen is an antigenic determinant (Figure 24-28). Almost antigenic macromolecules have many different antigenic determinants and are said to be multivalent; if two or more than of them are identical (as in a polymer with a repeating structure), the antigen is said to be polyvalent (Figure 24-29).
Figure 24-28
Antigen bounden to antibody. In this highly schematized diagram, an antigenic determinant on a macromolecule is shown interacting with the antigen-binding site of two dissimilar antibody molecules, ane of high affinity and one of low affinity. The antigenic (more than...)
Figure 24-29
Molecules with multiple antigenic determinants. (A) A globular poly peptide is shown with a number of dissimilar antigenic determinants. Different regions of a polypeptide chain usually come together in the folded structure to form each antigenic determinant (more...)
The reversible bounden reaction between an antigen with a single antigenic determinant (denoted Ag) and a unmarried antigen-binding site (denoted Ab) can exist expressed every bit
The equilibrium bespeak depends both on the concentrations of Ab and Ag and on the force of their interaction. Conspicuously, a larger fraction of Ab will become associated with Ag equally the concentration of Ag increases. The forcefulness of the interaction is mostly expressed equally the affinity constant ( K a ) (run across Figure 3-44), where
(the foursquare brackets indicate the concentration of each component at equilibrium).
The analogousness constant, sometimes called the association abiding, can be determined by measuring the concentration of free Ag required to make full half of the antigen-binding sites on the antibody. When half the sites are filled, [AgAb] = [Ab] and K a = one/[Ag]. Thus, the reciprocal of the antigen concentration that produces half the maximum bounden is equal to the affinity constant of the antibody for the antigen. Common values range from as low every bit five × x4 to every bit high as x11 liters/mole.
The affinity of an antibody for an antigenic determinant describes the strength of bounden of a single re-create of the antigenic determinant to a single antigen-binding site, and information technology is contained of the number of sites. When, withal, a polyvalent antigen, conveying multiple copies of the same antigenic determinant, combines with a polyvalent antibiotic, the binding strength is greatly increased because all of the antigen-antibiotic bonds must be broken simultaneously before the antigen and antibody can dissociate. As a result, a typical IgG molecule tin bind at least 100 times more strongly to a polyvalent antigen if both antigen-binding sites are engaged than if but 1 site is engaged. The total bounden force of a polyvalent antibody with a polyvalent antigen is referred to equally the avidity of the interaction.
If the analogousness of the antigen-bounden sites in an IgG and an IgM molecule is the same, the IgM molecule (with ten binding sites) volition have a much greater avidity for a multivalent antigen than an IgG molecule (which has two bounden sites). This departure in avidity, ofttimes x4-fold or more, is important because antibodies produced early in an allowed response usually take much lower affinities than those produced afterwards. Because of its loftier total avidity, IgM—the major Ig course produced early in allowed responses—tin can function finer even when each of its bounden sites has simply a low affinity.
And so far we have considered the full general structure and part of antibodies. Next we look at the details of their construction, as revealed by studies of their amino acid sequence and three-dimensional structure.
Light and Heavy Chains Consist of Abiding and Variable Regions
Comparison of the amino acid sequences of unlike antibody molecules reveals a striking characteristic with important genetic implications. Both light and heavy bondage have a variable sequence at their N-terminal ends just a constant sequence at their C-final ends. Consequently, when the amino acid sequences of many unlike κ chains are compared, the C-terminal halves are the same or evidence only pocket-size differences, whereas the N-concluding halves are all very different. Light bondage have a constant region about 110 amino acids long and a variable region of the aforementioned size. The variable region of the heavy chains (at their North-terminus) is also about 110 amino acids long, simply the heavy-chain constant region is near three or four times longer (330 or 440 amino acids), depending on the form (Effigy 24-30).
Figure 24-30
Constant and variable regions of immunoglobulin chains. Both light and heavy chains of an antibody molecule have distinct abiding and variable regions.
Information technology is the Northward-final ends of the light and heavy chains that come together to grade the antigen-bounden site (come across Effigy 24-21), and the variability of their amino acid sequences provides the structural basis for the diverseness of antigen-bounden sites. The diverseness in the variable regions of both light and heavy chains is for the most part restricted to three minor hypervariable regions in each chain; the remaining parts of the variable region, known as framework regions, are relatively constant. Only the 5–10 amino acids in each hypervariable region class the antigen-binding site (Figure 24-31). As a result, the size of the antigenic determinant that an antibiotic recognizes is generally comparably small-scale. It can consist of fewer than 25 amino acids on the surface of a globular protein, for example.
Effigy 24-31
Antibody hypervariable regions. Highly schematized drawing of how the three hypervariable regions in each calorie-free and heavy chain together form the antigen-binding site of an antibody molecule.
The Light and Heavy Chains Are Composed of Repeating Ig Domains
Both light and heavy chains are fabricated upward of repeating segments—each nearly 110 amino acids long and each containing one intrachain disulfide bond. These repeating segments fold independently to form compact functional units called immunoglobulin (Ig) domains. As shown in Figure 24-32, a light chain consists of i variable (V50) and 1 abiding (CL) domain (equivalent to the variable and constant regions shown in the top one-half of Figure 24-30). These domains pair with the variable (VH) and starting time constant (CH1) domain of the heavy chain to form the antigen-binding region. The remaining constant domains of the heavy chains course the Fc region, which determines the other biological properties of the antibody. Most heavy bondage have 3 constant domains (CH1, CH2, and CH3), but those of IgM and IgE antibodies accept 4.
Figure 24-32
Immunoglobulin domains. The low-cal and heavy chains in an antibody molecule are each folded into repeating domains that are similar to one another. The variable domains (shaded in blueish) of the light and heavy chains (VFifty and VH) make upwards the antigen-binding (more...)
The similarity in their domains suggests that antibody bondage arose during development by a serial of gene duplications, get-go with a primordial gene coding for a single 110 amino acrid domain of unknown function. This hypothesis is supported by the finding that each domain of the abiding region of a heavy chain is encoded by a split up coding sequence (exon) (Figure 24-33).
Figure 24-33
The system of the Deoxyribonucleic acid sequences that encode the constant region of an antibody heavy chain. 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, as well as intact antibody molecules, have been studied past x-ray crystallography. From these examples, we can sympathise the way in which billions of unlike antigen-bounden sites are constructed on a common structural theme.
Equally illustrated in Effigy 24-34, each Ig domain has a very like three-dimensional structure based on what is called the immunoglobulin fold, which consists of a sandwich of ii β sheets held together by a disulfide bail. We shall run across 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), comprise similar domains and hence are members of a very large immunoglobulin (Ig) superfamily of proteins.
Figure 24-34
The folded construction of an IgG antibody molecule, based on ten-ray crystallography studies. The structure of the whole protein is shown in the eye, while the structure 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 item set of three hypervariable regions, which are arranged in three hypervariable loops (see Figure 24-34). The hypervariable loops of both the lite and heavy variable domains are clustered together to form the antigen-binding site. Because the variable region of an antibody molecule consists of a highly conserved rigid framework, with hypervariable loops attached at 1 terminate, an enormous diversity of antigen-binding sites tin be generated by changing merely the lengths and amino acid sequences of the hypervariable loops. The overall three-dimensional structure necessary for antibody function remains constant.
X-ray analyses of crystals of antibiotic fragments bound to an antigenic determinant reveal exactly how the hypervariable loops of the light and heavy variable domains cooperate to form an antigen-binding surface in detail cases. The dimensions and shape of each different site vary depending on the conformations of the polypeptide chain in the hypervariable loops, which in plough are adamant past the sequences of the amino acid side chains 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 antibiotic (Figure 24-35). Smaller ligands tend to bind to deeper pockets, whereas larger ones tend to bind to flatter surfaces. In addition, the bounden site tin can modify its shape later antigen binding to better fit the ligand.
Figure 24-35
Antigen-binding sites of antibodies. The hypervariable loops of different VL and 5H domains tin combine to form a large diversity of binding surfaces. The antigenic determinants and the antigen-binding site of the antibodies are shown in cherry-red. Only ane antigen-binding (more...)
Now that nosotros take discussed the construction and functions of antibodies, nosotros are ready 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 unlike antibody molecules?
Summary
Antibodies defend vertebrates against infection by inactivating viruses and microbial toxins and by recruiting the complement system and various types of white blood cell to impale the invading pathogens. A typical antibody molecule is Y-shaped, with two identical antigen-binding sites at the tips of the Y and binding 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 cell development in the bone marrow, the antibiotic 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 every bit the membrane-leap antibodies.
A typical antibiotic molecule is equanimous of four polypeptide chains, two identical heavy chains and two identical lite chains. Parts of both the heavy and low-cal chains commonly combine to form the antigen-binding sites. There are five 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 course the tail (Fc region) of the antibody, which determines what other proteins will bind to the antibiotic and therefore what biological backdrop the antibody class has. Either type of lite chain (κ or λ) tin can be associated with whatsoever grade of heavy chain, merely the type of calorie-free chain does not seem to influence the properties of the antibody, other than its specificity for antigen.
Each light and heavy chain is composed of a number of Ig domains—β sheet structures containing about 110 amino acids. A calorie-free concatenation has i variable (VL) and 1 constant (CL) domain, while a heavy chain has one variable (VH) and 3 or four constant (CH) domains. The amino acrid sequence variation in the variable domains of both light and heavy chains is mainly bars to several small hypervariable regions, which protrude every bit loops at 1 end of the domains to form the antigen-bounden site.
Source: https://www.ncbi.nlm.nih.gov/books/NBK26884/
0 Response to "Drag the Images to Their Corresponding Class to Review the Structure and Function of Antibodies"
Post a Comment