Major Histocompatibility Complex Class I
From Proteopedia
Major Histocompatibility Complex (MHC) genes, and the proteins they specify, play centrally important roles in adaptive immune responses. MHC proteins contain grooves or sockets that are loaded with peptide fragments of intracellular proteins. The MHC proteins then carry these peptides to the outer surface of the cell, where thymus-derived ("T") lymphocytes examine them. When the peptides are deemed to be foreign by the T lymphocytes, appropriate immune defenses are activated. T lymphocytes are centrally important in all adaptive immune responses, including antibody production and the elimination of intracellular parasites, and their responses depend entirely on the MHC-presented peptides. Class I MHC proteins, in particular, reveal the presence of otherwise hidden intracellular parasites (such as viruses and some bacteria) by displaying peptide fragments of parasite proteins on the cell surface. For more detail, please see Wikipedia: Major Histocompatibility Complex.
The 3D structure of MHC proteins was one of the highest impact crystallographic strucures of all time. In order to appreciate why, some historical background is helpful.
Major Histocompatibility Complex (MHC) Class I: Historical Background
Major Histocompatibility Complex (MHC) refers to a complex of closely linked genes first identified in the early to mid-20th century as being the major factors in the rejection of living tissue allografts (grafts between members of the same species). It was these studies that gave MHC its name. Many other genes contribute to tissue allograft rejection in a minor way, and these were called minor histocompatibility genes. MHC genes code for MHC proteins that are the major antigens responsible for tissue allograft rejection. George D. Snell received one third of the 1980 Nobel Prize in Physiology or Medicine for his contributions to the identification and characterization of these genes. Of course many other researchers made crucial contributions and they are credited in Snell's Nobel Lecture. Jean Dausset received a third of the 1980 Nobel Prize in Physiology or Medicine for demonstrating the existence of MHC genes and proteins in humans, the latter being called Human Leukocyte Antigens (HLA). In mice, the most-used experimental model for studying MHC, the histocompatibility genetic loci were numbered H-1, H-2, H-3, and so forth. H-2 is the major histocompatibility locus, while all the others are minor. Both HLA and H-2 turned out to be large complexes of closely-linked genes.
Independently, in the early 1960's, Baruj Benacerraf and coworkers demonstrated the existence of immune response genes (Ir genes) that controlled the ability of an individual guinea pig's immune system to respond to simple synthetic amino acid polymers. Benacerraf was awarded one third of the 1980 Nobel Prize in Physiology or Medicine for discovering immune response genes. In the late 1960's, McDevitt and others found that the Ir genes were linked to MHC (for details, see Benacerraf's Nobel Lecture).
In 1975, Zinkernagel and Doherty made the surprising discovery that the ability of virus-specific T lymphocytes to recognize the virus, as virus-infected cells, depended upon the MHC genotype of the infected cells. The MHC had to match that present when the T lymphocytes were first activated by the virus. This "restriction" of antigen recognition by T cells was confirmed in many other systems. In 1996, Zinkernagel and Doherty were awarded the Nobel Prize in Physiology or Medicine for this discovery. By that time, the mechanism of the "restriction" they had observed was clear -- thanks to the 3D structure of MHC Class I.
3D Structure and Its Significance
By the mid-1980's, there was abundant evidence that the ability of T lymphocytes to recognize antigen is restricted by MHC. However, what this fundamentally important finding meant in terms of molecular mechanism was far from clear. Speculation about possible mechanisms raged for over a decade following Zinkernagel and Doherty's insight. But no experimental evidence available at the time was able to explain the "restriction". As an illustration, Figure 7 in Benacerraf's Nobel Lecture shows his thinking in 1980. The figure shows an "Ia molecule" hypothetically "specifically interacting" with an "antigen fragment". Note that although the genetic linkage between Ia (the molecule coded for by immune response genes) and MHC was well established, it was not yet clear that Ia was MHC. Benacerraf's thinking was correct, as far as it went, but the details were not yet available.
In 1987, Bjorkman and coworkers ...
(to be continued)
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Hannah Campbell, Eric Martz, Jaime Prilusky, Sandra B. Gabelli, Michal Harel
