Major Histocompatibility Complex
MHC displays peptides on the surfaces of cells, allowing the immune system to sense the infection inside
Major histocompatibility complex, with a displayed peptide in red. The portion crossing the membrane is not included in the structure and is shown schematically.Download high quality TIFF image
Viruses are insidious enemies, so we must have numerous defenses against them. Antibodies
are our first line of defense. Antibodies bind to viruses, mobilizing blood cells to destroy them. But what happens if viruses slip past this defense and get inside a cell? Then, antibodies have no way of finding them and the viruses are safe...but not quite.
Each cell has a second line of defense that it uses to signal to the immune system when something goes wrong inside. Cells continually break apart a few of their old, obsolete proteins and display the pieces on their surfaces. The small peptides are held in MHC, the major histocompatibility complex, which grips the peptides and allow the immune system to examine them. In this way, the immune system can monitor what is going on inside the cell. If all the peptides displayed on the cell surface are normal, the immune system leaves the cell alone. But if there is a virus multiplying inside the cell, many of the MHC molecules carry unusual peptides from viral proteins, and the immune system kills the cell.
Like many proteins used in the immune system, MHC is composed of several functional parts connected by flexible joints. The structure shown here, PDB entry 1hsa
, only shows the part found on the outside of the cell. The large chain colored orange has a groove at the top, which binds to the peptide, colored red. A smaller chain, colored pink, stabilizes the structure. In the whole protein, the orange chain extends down and crosses the cell membrane at the bottom, attaching the protein to the surface of the cell. This portion of the molecule, however, is too flexible for study by x-ray crystallography and was removed for the analysis.
MHC in Action
Our itchy reaction to poison ivy is caused by the MHC system. The resins on poison ivy leaves react with proteins in the skin. These poisoned cells then break the proteins into pieces and display them using MHC molecules. The itchy rash is caused when the immune system attacks the problem. Even more serious, MHC is the cause of tissue rejection during skin grafts and organ grafts. This is how the protein got its name: the term histocompatibility refers to the difficulty of finding compatible grafts between a donor and a patient. Each person has their own collection of MHC molecules. There are hundreds of different kinds, but each person only has four types (two from each parent). If you graft a piece of skin that has a different collection of MHC types, they will trigger the immune system to destroy the cells. So the trick is to find a compatible donor, such as a relative, who has a similar collection of MHC molecules.
The Cancer Connection
There is growing evidence that the MHC system is also important in the natural fight against cancer in your body. Cancer cells, like normal cells, display pieces of their own proteins on their surface. So, if any of these proteins carry recognizable cancer mutations, this provides a signal to the immune system that something is wrong.
Types and Terminology
Two major types of MHC are used in your body. Class I MHC is found on the surface of most cells, where it protects us from viral infection. An example is shown on the left, from PDB entry 1hsa
. Class II MHC, on the other hand, is found in specialized antigen-presenting cells that have the job of picking up proteins around the body and stimulating the immune system when they find a strange peptide to display. Like class I MHC, class II MHC is found tethered to the cell surface and it has a pocket that displays small peptides. It is different, however, in a few details. Both chains of class II MHC have portions that cross the membrane and the binding site is formed in a groove between the two chains. An example is shown here on the right from PDB entry 1dlh
. As is often the case in science, there is also some terminology to watch out for: human MHC molecules are often named HLA, for human leucocyte antigen.
A Family of Folds
Many immune system proteins are built of a similar folding unit, composed of a sandwich of beta sheets (shown with blocky arrows in cartoon diagrams) locked together with a disulfide bridge between two cysteine amino acids in the center. This common domain structure shows up again and again as you look through the immune system proteins in the PDB. Three examples are shown here: the T-cell receptor (1tcr
) which has four of these domains; an antibody (1igt
) with 12 of these domains; and MHC (2hla
) with two of these domains. The similarity of the amino acids that form these tight units indicates that many immune system proteins have evolved from a similar ancestor protein.
For more information on MHC from a genomic perspective, see the Protein of the Month at the European Bioinformatics Institute
Exploring the Structure
The entire MHC system poses a problem: each cell has thousands of different peptides to display, but each cell only builds a few types of MHC. The solution to this dilemma was revealed in the early structures of MHC with different peptides. The two structures shown here, entry 2vaa
on the left and entry 2vab
on the right, have peptides from two different viruses bound to the same MHC. Another similar series can be found in PDB entries 1hhg
, and 1hhk
. Looking at these structures, you can see that the peptide, which is nine amino acids long, is held in an extended conformation in a groove between two long alpha helices, as shown in the upper pictures. The MHC protein grips the peptide at each end and at a tyrosine in the middle, as shown by the yellow stars. Notice that these three positions are similar in the two structures. The peptide is anchored to MHC at these points, but the other amino acids extend outward, away from the protein. In the Molecule of the Month on T-cell receptors
, you can look at how the immune system recognizes these exposed portions of the peptides.
These illustrations were created with RasMol. You can create similar pictures by clicking on the accession codes here and picking one of the options for 3D viewing.
Related PDB-101 Resources
- S. Sell (2001) Immunology, Immunopathology and Immunity. ASM Press, Washington, D. C.
- K. Natarajan, H. Li, R. A. Mariuzza and D. H. Margulies (1999) MHC Class I Molecules, Structure and Function. Reviews in Immunogenetics 1, 32-46.
- I. A. York and K. L. Rock (1996) Antigen Processing and Presentation by the Class I Major Histocompatibility Complex. Annual Review of Immunology 14, 369-396.
- M. Matsumura, D. H. Fremont, P. A. Peterson and I. A. Wilson (1992) Emerging Principles for the Recognition of Peptide Antigens by MHC Class I Molecules. Science 257, 927-934.
February 2005, David Goodsell