Immunoglobulin Structure and Function
F I G U R E 3 5 - 1 3
(Also see color figure.) Major histocompatibility complex (MHC) proteins class I. The MHC class I proteins of
antigen-presenting cells comprise two polypeptide chains,
The a-polypeptide (~360 residues) (helices red, /1
sheets dark yellow, and loops gray) has two extracellular domains shown here ( «1 and /12), and a transmembrane and
intracellular domain (a3, not shown) The a3 domain is structurally similar to the immunoglobulins. The non-MHC
gene-related protein, /32-microglobulin (99 residues), is shown in green on the right side of each structure. The other
subunits of the complex that are involved in T-cell receptor recognition are not shown. The figures are derived from the
coordinates published in the Protein Data Bank files 1AGD and 1AGB. (A) HIV-1 GAG peptide GGKKKYKL
presented on the surface of the MHC class II protein. The peptide is shown with the residues spacefilled, the Lys residue,
K is colored cyan and marked by the arrow. (B) HIV-1 GAG peptide GGRKKYKL presented on the surface of the MHC
class II protein. The peptide is shown with the residues spacefilled, the Arg residue, R is colored cyan and marked by an
arrow. Note that the position of the a helix (part of the
a \
domain) immediately adjacent to the Arg or Lys residues has
undergone a change in position (conformation change) and has a small helical segment (lower left) as a result of this
single-amino-acid substitution. Such sensitivity to small changes in antigen structure is critical to specificity.
cell. A third domain, a3, crosses the membrane and is
exposed on the inside of the cell. The second polypeptide
is /3-microglobulin, a protein that is functionally involved
in antigen presentation by MHC I protein. This molecule is
not encoded by genes within the MHC locus. Two MHC I
protein structures with bound, virus-derived peptides have
been determined by x-ray crystallography. The two MHC I
proteins were identical, but the bound peptides differed
in that an Arg residue had replaced a Lys residue in the
-residue peptide from the HIV-1 GAG protein. The pep-
tide that is bound to the MHC I complex “sits” in a groove
formed by the
1 and
a !
domains. The difference between
these two peptides of one basic amino acid is sufficient to
cause a movement of an
helix in the
domain of the
polypeptide. The dramatic change in conforma-
tion that is produced by a small change in antigen structure
illustrates the almost absolute requirement for comple-
mentarity that underlies immunological specificity. Such
stringent requirements enable the self/nonself distinction
to be almost flawlessly in virtually all situations. The two
MHC I protein structures are shown in Figure 35-13.
Action by the cytotoxic T cell requires interaction
between the CD
+ T cell and the MHC I antigen-
presenting cell. The TcR consists of two polypeptides,
chains. The TcR is structurally related to im-
munoglobulin Fab fragments and contains both V and
C domains. Recognition of the MHC I peptide com-
plex by a TcR occurs through contact between the TcR
chains and MHC I
chains. A complex showing the
MHC I protein and a peptide derived from the T-cell lym-
photropic virus HTLV-I is given in Figure 35-14. The re-
gions of contact between TcR molecules and the MHC I
molecule vary and depend on the structure of the peptide
antigen. The TcR on the cytotoxic T cell is associated
with the CD3 complex, the transmembrane signaling
Stimulation of B cells to proliferate and differentiate
into memory and plasma cells depends on epitope bind-
ing to epitope-specific receptors on CD4+ T-helper cells.
Transmembrane signaling then requires the coreceptor
protein CD3. Binding of the T-cell receptor to the antigen-
presenting B cell occurs via the TcR that interacts with
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