section 35.6
Immunoglobulin Structure and Function
813
the proteins with this motif are classified as belonging to
the immunoglobulin superfamily.
Immunoglobulin superfamily members are chacter-
ized by a common /1-sheet structural motif. Each of the
P
sheets consists of several
p
strands. The
P
strands within
each sheet are arranged antiparallel to each other, with each
antiparallel strand connected to the next by a hairpin turn.
The overall “up and down” arrangement of these strands
is sometimes designated a Greek key topology based on
the occurrence of a similar pattern on ancient pottery. Two
P
sheets are derived from 110- to 120-amino-acid residues
of polypeptide chain and are folded in such a way that
they are frequently described as a
“P
sandwich.” This
“p
sandwich” forms the structural domain that is the
building block of the immunoglobulin molecules in the
Ig superfamily (Figure 35-5).This motif is also called
the
immunoglobulin fold.
In the four polypeptide chains of the immunoglobulin
molecules(IgG, IgE, and IgD) there are 12 /1-sandwich do-
mains. Two domains are formed from each light chain and
four domains are formed from each heavy chain. An ex-
tended amino acid segment connects adjacent /
1
-sheet do-
mains of each polypeptide chain that creates a flexible fold
between the adjacent /1-sandwich domains (Figure 35-6;
see color plates). An IgG schematic structure, a cartoon
secondary structure, and a space-filling tertiary structure
based on x-ray crystallography of immunoglobulins are
shown in Figure 35-7. The relationships between the
heavy and light chains and the immunoglobulin /
1
-sheet
motifs of the immunoglobulin G molecule are illustrated
in Figure 35-7B.
The immunoglobulin molecule can also be divided into
two regions that are both structurally and functionally dis-
tinct. These regions are designated the constant and vari-
able regions (Figure 35-7A). The immunoglobulin heavy
chains contain three regions with relatively constant amino
acid sequences. These are designated CHI, CH2, andCH3.
Each heavy chain also contains a region notable for its se-
quence variability: the “variable region” (VH). Within the
variable region are three shorter segments in which the
amino acid sequences are highly variable; these are desig-
nated
hypervariable regions
and are the basis for antigen
recognition. The immunoglobulin light chains consist of
only two structurally and functionally distinct regions, one
“constant region” (CF) and one variable region (VF). As
in the heavy chain, the variable region of the light chain
contains three hypervariable regions that are involved in
antigen recognition.
The two heavy and two light chains of the immunoglob-
ulin molecule form a tertiary structure resembling the
letter Y (Figure 35-7). Disulfide bonds within each of the
variable and constant domains stabilize the immunoglobu-
FIGURE 35-6
(Also see color figure.) Pairs of immunoglobulin motif structures (see
Figure 35-7) connected by “tether” polypeptide that creates a flexible fold.
The disulfide bridges that connect the
f}
sheets of the /3 sandwich are
shown as yellow space-filling residues. Each IgG molecule contains six
such folds arranged so that heavy and light chain folds partially wrap
around each other (Figure 35-7B,C). The ribbon model shown is from a
x-ray crystallographic structure of a Fab fragment. The figure is derived
from the coordinates published in the Protein Data Bank file, 2FPB.
lin structures. The VF and CF domains of each light chain
are linked to the VH and CH domains of the heavy chain via
a single disulfide bridge. The region connecting the disul-
fide linked VH and CHI to the CH2 and CH3 domains
of the heavy chains forms a hinge in the immunoglobulin
molecule. The two arms of the Y-shaped immunoglobulin
molecule are flexible and when “open” can be as well de-
scribed as a T shape. The immunoglobulin heavy chains
are linked to each other via two disulfide bridges, both
located within the hinge region of the immunoglobulin
molecule.
Amino acid residues within the hinge region of the
heavy chains are accessible to proteolytic enzymes. Cleav-
age within this region by the enzyme papain results in the
formation of three products; one consists of the CH2 and
