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IMMUNOGLOBULIN'S

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Immunoglobulins :

Structure and Functions

Definition: Glycoprotein molecules that are produced by 20% of total plasma cells in response to an immunogen and which function as antibodies
Element of adaptive immune mechanism
Better known as antibody or antigen binding protein
It recognize the foreign objects

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General Functions of Immunoglobulins

Ag binding

Can result in protection
Valency

Effector functions

Fixation of complement
Binding to various cells
Usually requires Ag binding

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Structure of immunoglobulin

Two identical heavy (H) chains (400 amino acids) and two identical light (L) chains (200 amino acids) combine to form this Y-shaped antibody molecule

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Heavy chains

The heavy chains each have four domains

Variable domains (VH)
Constant domains (CH1,2,3)
Polypeptides of about 50000 molecular weight

The heavy chains each have four domains. The amino terminal variable domains (VH) are at the tips of the Y. These are followed by three constant domains: CH1, CH2, and the carboxy terminal CH3, at the base of the Y's stem.

A short stretch, the switch, connects the heavy chain variable and constant regions. The hinge connects CH2 and CH3 (the Fc fragment) to the remainder of the antibody (the Fab fragments).

The two identical protein chains in an antibody molecule that contain the most amino acids and, therefore, have the greater molecular weight.

An immunoglobulin fold is a common all-β protein fold that consists of a 2-layer sandwich of ~7 antiparallel β-strands arranged in two β-sheets.

The backbone switches repeatedly between the two β-sheets. Typically, the pattern is (N-terminal β-hairpin in sheet 1)-(β-hairpin in sheet 2)-(β-strand in sheet 1)-(C-terminal β-hairpin in sheet 2). The cross-overs between sheets form an "X", so that the N- and C-terminal hairpins are facing each other.

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Light chain

The light chains are constructed of two domains

Variable (VL)
Constant (CL)
Polypeptides of about 25000 molecular weight.

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Structure of immunoglobulin

The fragment antigen binding (Fab fragment)
The fragment crystallizable region (Fc region)
Antibodies bind to antigens by reversible, non-covalent interactions.

The fragment antigen binding (Fab fragment) is a region on an antibody which binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope—the antigen binding site—at the amino terminal end of the monomer. The two variable domains bind the epitope on their specific antigens.

The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and some proteins of the complement system. This property allows antibodies to activate the immune system. In IgG, IgA and IgD antibody isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains of the antibody's two heavy chains; IgM and IgE Fc regions contain three heavy chain constant domains (CH domains 2-4) in each polypeptide chain

Antibodies are capable of binding a wide variety of antigens, including macromolecules and small chemicals. The reason for this is that the antigen - binding region of antibody molecules forms a flat surface capable of accommodating many different shapes. Antibodies bind to antigens by reversible, noncovalent interactions, including hydrogen bonds and charge interactions.

The parts of antigens that are recognized by antibodies are

called epitopes, or determinants. Different antigenic determinants may be recognized based on sequence (linear determinants) or shape (conformational deter-

determinants). Some of these epitopes are hidden within antigen molecules and are exposed as a result of a physicochemical change (neodeterminants).

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Disulfide bonds

Bonds between two amino acids result of the SH (sulfhydryl) group of one amino acid covalently bonding to the SH group of another amino acid
Stronger than hydrogen bonds
Eg. Hair proteins are held together by disulfide bonds

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Functional Consequences:

(VH) and (VL) are positioned to stereo chemically react with antigen
The stem is good for mediate effector functions

The structural features discussed so far have important functional consequences. The variable regions of both the heavy and light chains, (VH) and (VL), lie at the tips of the Y, where they are positioned to stereochemically react with antigen. The stem of the Y projects in a way to efficiently mediate effector functions such as the activation of complement. Its CH2 and CH3 domains bulge to facilitate interaction with effector proteins.

Geometric fit and a chemical (electrostatic charge) fit, often called complementarity -- the antibody has + charge where the antigen is -, and the antibody has knobs where the antigen has indentations

Constant fragment. The portion of an antibody molecule that carries out the biological activities of that class of antibody. Biological activity includes binding to receptors on phagocytes and activating the classical complement pathway. The amino acid sequence of the Fc portion of an antibody is the same for every antibody in that class.

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Heavy Chain

Heavy chains are distinct for each Of the

five Ig classes or isotypes and are

designated γ, α, μ, δ, ε for the respective

classes of Ig, namely IgG , IgA

IgM, IgD, IgE.

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Light Chain

L chains are one of two types

Designated κ and λ and

only one type is found in Ig.

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L and H chains are subdivided into variable and constant regions.

The regions are composed of three-dimensionally folded, repeating segments called domains.

An L chain consists of one variable (VL) and one constant (CL) domain.

Most H chains consist of one variable (VH) and three constant(CH) domains(IgG and IgA have three CH domains, whereas IgM and IgE have four).

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Functions of Variable and Constant Regions:

The varible regions are responsible

for antigenbinding ,whereas the constant

regions are responsible for various

biologic functions eg, complement

activation and binding to cell surface

receptors.

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The variable regions of both L

and H chains have three extremely

variable (“hyper variable”) amino

acid sequence at the amino-

terminal end that form the antigen-

binding site.

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Hinge Region

The units of heavy chains contain an extended peptide sequenc bet the ch1 and ch2 domins that has no homology called hinge region
Two disulfide bonds in the hinge region unite the two heavy chains
Proline rich region
The hinge allows the two antigen-binding Fab regions of each antibody molecule to move.
Hinge region rich in proline residues and is flexible, giving segmental flexibility

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Immunoglobulin Fragments: Structure and Functions

Ag Binding

Complement Binding Site

Placental Transfer

Binding to Fc Receptors

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Human Immunoglobulin Classes

IgG - Gamma heavy chains
IgM - Mu heavy chains
IgA - Alpha heavy chains
IgD - Delta heavy chains
IgE - Epsilon heavy chains

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Structures and Properties of Immunoglobulin's:

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IgG

Structure - Monomer

Four Types IgG1,IgG2,IgG3 and IgG4

IgG1, IgG2 and IgG4

IgG3

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IgG: Properties:

Major serum (present in blood plasma, tissue fluids) Ig about 80%
Major Ig in extravascular spaces
The only antibody to cross the placental barrier
Fixes complement (IgG3,IgG1,IgG4) by activate complement proteins
Secrete early milk in mammary glands.
Binds to Fc receptors

Phagocytes - opsonization
NK cells –
The only antibody capable of crossing the placenta to give passive immunity to the fetus.

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IgM

Structure

Pentamer

composed 5 H2L2 units plus one molecule of J chain

Extra domain (C_H4)
J chain

(C_H4)

J Chain

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IgM: Properties

3rd highest serum Ig 5-10%
Largest IG with 10 binding sites
First Ig made by fetus and B cells
Produced early in the primary response
The most efficient Ig
Fixes complement
B cell surface Ig

Tail Piece

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IgA

Structure

Serum - monomer
Secretions (sIgA)
Dimer , IgA molecule consists of two H2L2 units plus one molecule each of J chain and secretory component(SC or SP)

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