section

35.6

Immunoglobulin Structure and Function

821

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,

a

and

fj.

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

8

-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

a

1 and

a !

domains. The difference between

these two peptides of one basic amino acid is sufficient to

cause a movement of an

a

helix in the

a

1

domain of the

MHC I

a

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

8

+ T cell and the MHC I antigen-

presenting cell. The TcR consists of two polypeptides,

a

and

ft

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

a

chains and MHC I

a

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

protein.

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