Structure of Major Histocompatibility Complex (MHC) 4.56/5 (9)

Structure of Major Histocompatibility Complex (MHC)


Class I and Class II MHC antigens have somewhat different structure.

MHC Class I molecules

  • MHC Class I molecules in both human and mouse consist of two polypeptide chains that dramatically differ in size.
  • The larger (α) chain has a molecular weight of 44 kDa in humans and 47 kDa in the mouse, and is encoded by an MHC Class I gene.
  • The smaller chain, called β-2 microglobulin, has a molecular weight of 12 kDa in both species, and is encoded by a nonpolymorphic gene that is mapped outside of the MHC complex.
  • There are no known differences in the structure of the human MHC Class I antigen a chains encoded by the HLA-A locus compared to those encoded by the HLA-B or the HLA-C loci, or in the structure of the murine MHC Class I antigen a chains encoded by the H-2K locus compared to those encoded by the H-2D or H-2L loci.
MHC Class I molecules


Figure: Structure of MHC Class I antigens

Regardless of which of these loci codes it, the a chain can be subdivided into the following regions, or domains:


  1. the peptide-binding domain;
  2. the immunoglobulin-like domain;
  3. the transmembrane domain; and
  4. the cytoplasmic domain.
  • The peptide-binding domain is the most N-terminal; it is the only region of the molecule where allelic differences in the amino acid sequence can be localized.
  • As seen from its name, the peptide-binding domain of the molecule includes the site to which antigenic peptides bind.
  • It makes much sense to have this site exactly where the allelic differences are, because different MHC alleles accommodate peptides better or worse, thus influencing on the magnitude of the T-cell response.
  • X-ray crystallography showed that the peptide-binding site in the MHC Class I molecules looks like a cleft that has a ‘‘floor’’ and two ‘‘walls’’ formed by spiral shaped portions of the alpha chain, called alpha 1 and alpha 2.
  • Since the ‘‘floor’’ of the peptide-accommodating cleft is closed, only relatively small peptides, consisting of 9 to 11 amino acid residues, can be ‘‘stuffed’’ there.
  • The immunoglobulin-like domain is structurally conserved, and resembles a domain of an antibody C-region.
  • It contains the binding site for the T-cell accessory molecule CD8.
  • The transmembrane and the cytoplasmic domains ensure that the alpha chain spans the membrane and is properly expressed by the cell.
  • The β-2-microglobulin chain is also vitally important for the proper expression of the alpha chain.
  • There are some mutant lymphoid cell lines (notably Daudi) that do not express MHC Class I molecules because of the defect in the β-2-microglobulin gene.

Class II MHC molecules

  • Class II MHC molecules in both human and mouse consist of two polypeptide chains that have a similar, albeit not identical size.
  • One of them is called alpha (α) and the other beta (β).
  • The molecular weight of the a chain is 32–34 kDa, and of the b chain 29–32 kDa.
  • A separate gene controls each of the chains.
  • Thus, the murine I-A locus actually consists of the Iα and Iβ genes, the human HLA-DR locus of the HLA-DRα and HLA-DRβ, etc. Both the α and the β genes are polymorphic.
  • The β genes of some of the MHC Class II loci can be tandemly duplicated, so, instead of one gene per homologous chromosome, a cell can have two or three.
  • Because of that, one cell can simultaneously express more than two allelic products of each of the MHC Class II loci.
  • For example, a cell can express allelic products of its HLA-DR molecule that can be identified as HLADRα1– HLA-DRβ1; HLA-DRα2 – HLA-DRβ2; HLA-DRα1 – HLA-DRβ2; HLA-DRα2 – HLA-DRβ1; etc.
  • Overall, one cell can simultaneously express as many as 20 different MHC Class II gene products because of this tandem duplication phenomenon.
Structure of MHC Class II antigens
Figure: Structure of MHC Class II antigens

MHC Class I and Class II Molecules

  • The structure of the a and the b chains of the MHC Class II molecules resembles that of the alpha chain of the MHC Class I molecules in that the former can be also divided into the peptide-binding, the immunoglobulin-like, the transmembrane and the cytoplasmic domains.
  • One important difference, however, is that the peptide-binding cleft in Class II molecules is formed by both alpha and beta chains.
  • Although positioned close to each other in space, the spirals of the alpha and the beta chains that form the cleft are not physically bound to each other.
  • Because of that, the ‘‘floor’’ of the peptide-accommodating cleft in Class II MHC molecules is ‘‘open,’’ or ‘‘has a hole’’ in it.
  • That allows MHC Class II molecules to accommodate peptides that are larger than those that fit MHC Class I molecules.
  • The immunoglobulin-like domain of the MHC Class II molecules contains the binding site for a T-cell accessory molecule, CD4.
  • This site cannot bind the above-mentioned CD8 molecule.

Structure of Major Histocompatibility Complex (MHC)



Structure of Major Histocompatibility Complex (MHC)

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