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MHC Class I proteins

Thursday 10 November 2005

Class I MHC molecules are expressed on all nucleated cells and platelets. They are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C.

Each of these molecules is a heterodimer, consisting of a polymorphic α, or heavy, chain (44-kD) linked noncovalently to a smaller (12-kD) nonpolymorphic peptide called β2-microglobulin, which is not encoded within the MHC. The extracellular region of the heavy chain is divided into three domains: α1, α2, and α3.

Crystal structure of class I molecules has revealed that the α1 and α2 domains form a cleft, or groove, where peptides bind to the MHC molecule.

Biochemical analyses of several different class I alleles have revealed that almost all polymorphic residues line the sides or the base of the peptide-binding groove.

As a result, different class I alleles bind and display different peptide fragments. In general, class I MHC molecules bind and display peptides that are derived from proteins, such as viral antigens, synthesized within the cell.

The generation of peptide fragments within the cells, and their association with MHC molecules and transport to the cell surface, is a complex process.

Involved in this sequence are proteolytic complexes (proteasomes), which digest antigenic proteins in the cytoplasm into short peptides, and transport proteins, which ferry peptide fragments from the cytoplasm to the endoplasmic reticulum.

Within the endoplasmic reticulum, peptides bind to the antigen-binding cleft of newly synthesized class I heavy chains, which then associate with β2-microglobulin to form a stable trimer that is transported to the cell surface for presentation to CD8+ cytotoxic T lymphocytes.

In this interaction, the TCR recognizes the MHC-peptide complex, and the CD8 molecule, acting as a coreceptor, binds to the nonpolymorphic α3 domain of the class I heavy chain. CD8+ cytotoxic T cells can recognize viral (or other) peptides only if presented as a complex with self-class I antigens, and therefore CD8+ T cells are said to be class I MHC-restricted.

In the eyes of T cells, self-MHC molecules are those that they "grew up with" during maturation within the thymus. Because one of the important functions of CD8+ T cells is to eliminate viruses, which may infect any nucleated cell, it makes good sense to have widespread expression of class I HLA molecules.

References

- Robbins