The Major Histocompatibility Complex (MHC), known in humans as the Human Leukocyte Antigen (HLA), is the immune system’s primary method of communication. These molecules act as peptide presenters, displaying small protein fragments derived from within the cell to surveillance T-cells. This presentation allows the immune system to distinguish between the body’s healthy components and foreign invaders, such as viruses or bacteria. MHC molecules must successfully bind and present a vast variety of peptides from millions of potential pathogens. This capability relies on structural flexibility, degenerate binding rules, and a sophisticated genetic strategy.
The Flexible Architecture of the MHC Binding Groove
The ability of MHC molecules to bind diverse peptides starts with the unique physical structure of the binding groove. This groove is a shallow, open-ended trough formed by two alpha-helical walls atop a beta-sheet floor. This architecture provides structural freedom, accommodating a wide range of peptide shapes.
Structural differences exist between the two main classes of MHC molecules, dictating the length and presentation style of their peptides. Class I molecules, found on nearly all nucleated cells, have a binding groove closed at both ends by conserved amino acid residues. This closure forces the peptides to be relatively short, typically between eight and ten amino acids in length.
Class II molecules are primarily expressed on specialized immune cells like dendritic cells and macrophages. They possess a groove that is open at both ends, permitting them to bind much longer peptides, usually between twelve and twenty-five amino acids. The peptide sequence can extend beyond the confines of the groove, allowing greater flexibility in the size and sequence of the presented fragment.
The walls of both Class I and Class II grooves are relatively non-discriminatory toward the middle portion of the bound peptide. This lack of strict chemical requirement allows for significant variation in the amino acid sequence exposed to the T-cell receptor. The broad, shallow nature of the groove allows a single MHC molecule to associate with a multitude of different protein fragments.
Anchor Residues and Peptide Fit
Although the MHC binding groove is structurally flexible, the binding process is not random. It operates on the principle of degenerate binding, which establishes minimal rules for stable association. The peptide is secured within the groove not by its entire sequence, but by a small number of specific amino acids called anchor residues.
Anchor residues are situated at defined positions along the peptide sequence and must fit into complementary sub-pockets on the floor of the MHC groove. For MHC Class I, these anchors are typically found at the second and the last position of the nonamer peptide. The chemical properties of these residues must match the chemical environment of the corresponding pocket in the specific MHC molecule.
A single MHC molecule can bind thousands of different peptides if they share the same binding motif, defined by the required chemical nature of the anchor residues. The amino acids situated between the anchors are free to vary widely, as they project upward and do not directly contribute to complex stability. These variable residues are recognized by the T-cell receptor, making them the immunological determinant.
The identity of the binding motif is determined by the specific allele of the MHC molecule. This allele-specific requirement ensures that while one MHC molecule can bind many peptides, it does so according to its unique set of chemical preferences. This system provides a stable platform for T-cell recognition while maximizing the range of peptides presented by any single MHC variant.
Genetic Strategy of Polymorphism and Polygeny
The ability of the immune system to bind a variety of peptides at the population level is secured by the evolutionary genetics of the MHC. This strategy relies on two concepts: polygeny and polymorphism.
Polygeny
Polygeny refers to the presence of multiple, distinct MHC genes within the genome of a single individual. Humans possess multiple genes for both Class I and Class II molecules.
Humans possess:
- Three separate genes for Class I molecules (HLA-A, HLA-B, and HLA-C).
- Several genes for Class II molecules (HLA-DP, HLA-DQ, and HLA-DR).
Since an individual inherits a full set of these genes from each parent and expresses them simultaneously, a single person can express six different Class I molecules and up to twelve different Class II molecules. This ensures that every cell has multiple avenues for presenting peptides, significantly increasing the total repertoire of fragments the immune system can survey.
Polymorphism
Polymorphism is the most profound contributor to the MHC’s vast peptide-binding capacity across the human population. The MHC genes are the most polymorphic genes in the entire human genome, meaning there are thousands of different versions, or alleles, of each gene available in the species. Allelic variation is heavily concentrated in the amino acids that form the peptide-binding groove.
The extreme diversity of MHC alleles means that virtually every person expresses a unique combination of MHC molecules with differing binding motifs. If a new pathogen emerges, its specific peptides may fail to bind to the MHC molecules of some individuals. However, due to the massive allelic diversity, it is highly probable that at least one person’s MHC molecules will possess the correct binding motif to present the pathogen’s peptides to T-cells. This collective genetic strategy ensures that species-wide susceptibility to any single infectious agent is unlikely, protecting the population as a whole.