An
Introduction to
Immunoglobulin Structure
David Marcey
© 2006
I.
Introduction
II. Tetramer Structure
III. The Immunoglobulin Fold
IV. Variable Region Structure
V. References
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I.
Introduction
To
the left is a model of an intact IgG1 immunoglobulin (Padlan, 1994),
which can serve as a standard as we begin investigating the basics
of immunoglobulin structure. Two identical heavy
(H) chains and two identical light (L)
chains combine to form this Y-shaped antibody molecule.
Before discussing structural aspects of the H2L2
tetramer, let's examine the light and heavy chains separately.
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
plus
CH3
(the Fc fragment) to
the remainder of the antibody (the Fab fragments).
One
Fc
and two identical Fab fragments
can be produced by proteolytic cleavage of the hinge
in an intact antibody molecule.
The light
chains are
constructed of two domains, variable (VL)
and constant (CL),
separated by a switch.
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II.
Tetramer Structure
Two disulfide
bonds in the hinge region,
between cys235 and
cys238 pairs,
unite the two heavy
chains.
The light
chains are coupled to the heavy
chains by two additional disulfide
bonds,
between cys229s
in the CH1
domains and
cys214s
in the CL
domains.
Carbohydrate
moieties are
attached to asn306
of each CH2,
generating a pronounced bulge in the stem of the Y.
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 (see below). 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.
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III.
The Immunoglobulin Fold
A. The Constant
Domain Fold
Each domain in an antibody molecule has a similar structure
of two beta sheets packed tightly against each other in a compressed
antiparallel beta barrel. This conserved structure is termed the immunoglobulin
fold. At
left is an immunoglobulin
fold of a CL
domain containing a 3-stranded sheet
packed against a 4-stranded sheet.
The fold is stabilized by hydrogen
bonding between the beta strands of each sheet, by hydrophobic
bonding between
residues of opposite sheets in the interior, and by a
disulfide
bond between the
sheets.
The 3-stranded
sheet comprises strands C,
F, and
G,
and the 4-stranded
sheet has strands A,
B, E,
and D.
B. The Variable
Domain Fold
The folds
of variable domains have 9 beta strands arranged in two sheets of
4 and 5 strands.
The 5-stranded
sheet is structurally homologous to the 3-stranded
sheet of constant domains, but contains the extra strands C'
and C''.
The remainder of the strands (A,
B, C, D,
E, F,
G)
have the same topology and similar structure as their counterparts
in constant domain immunoglobulin folds.
A
disulfide
bond
links strands B and F
in opposite sheets, as in constant domains.
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IV.
Variable Region Structure
The variable domains of both light and heavy immunoglobulin
chains contain three hypervariable loops, or complementarity-determining
regions (CDRs). Shown at left are the three CDRs of aVL
domain (CDR1,
CDR2, CDR3).
These CDRs are clustered at one end of the beta barrel. The CDRs are
loops that connect beta strands B-C,
C'-C'',
and F-G
of the immunoglobulin fold (see above).
The VH
and VL domains
at the tips of antibody molecules are closely packed (see Tetramer
Structure, above) such that the six
CDRs (3 on each domain) cooperate in constructing a surface for antigen-specific
binding.
This is shown at left for a monoclonal antibody (IgG1) (Fischmann,
et al., 1991). Residues
in all six CDR's (VL
CDR1,
CDR2, CDR3
and VH
CDR1,
CDR2, CDR3)
project from the distal surface of the antibody tip, in position to
recognize and bind antigen.
The residues in
the CDRs vary from one immunoglobulin molecule to the next, imparting
antigen specificity to each antibody. For more information on antibody
binding antigenic molecules, see Antibody
Recognition of Antigen.
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V.
References
Fischmann, T.O.,
Bentley, G.A., Bhat, T.N., Boulot, G., Mariuzza, R.A., Phillips, S.E.V.,
Tello, D., and R.J. Poljak (1991). Crystallographic Refinement of
the Three-dimensional Structure of the FabD1.3-Lysozyme Complex at
2.5-Å Resolution. J. Biol. Chem. 266: 12915-12920.
Padlan,
E. (1994) Anatomy of the Antibody Molecule. Molecular Immunology
31: 169.
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