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Nature cover of MHC structure (1987)

Nature cover of MHC 3D structure

Sometimes in science a picture paints a thousand words. This image is the first to be unveiled of a crystallised protein molecule belonging to the major histocompatibility complex (MHC). In 1987 immunologists understood that the immune response to infection depended on combining the foreign proteins of viruses or bacteria with MHC molecules, and displaying the combination on the surface of cells. By using a system that depended on dual recognition, the immune system could learn what was ‘self’ and ignore it, while destroying what was ‘non-self’. Because each individual has their own unique set of MHC molecules, the MHC molecules in the donor tissue of a transplanted organ look like an infection. The immune response to these foreign tissue types was the main reason why organ transplants were rejected.

But how the two parts used in recognition, one from the infection and one from the host, were combined was a biochemical mystery. Did they have to be on the same cell, did they have to be seen in a specific sequence, did they have to be linked?

The particular HLA chosen for this study is called HLA-A2 and was the first human leucocyte antigen to be discovered, in 1958. It was not until 1987 that Pamela Bjorkman, then a postdoc researcher working with Jack Strominger and Don Wiley, solved its complex, three-dimensional structure and published two seminal scientific papers in the 8th October issue of Nature – which put the X-ray-crystallography image on its front cover.

The resulting picture, with a groove running along the top of the molecule formed by two long alpha-helical protein chains, immediately resolved the many conflicting theories of antigen presentation. The alpha chains act like a set of molecular pincers gripping short stretches of peptide derived from foreign antigens, allowing them to be “presented” to the immune system’s T-cells. This recognition had to be on one cell, to occur in a simultaneous process and depended on physical linkage. 

Between the two alpha helices there was a now famous “extra density” area of the crystal structure, revealed by this detailed X-ray analysis of the protein molecule. This extra dense region was interpreted to mean that the crystals of HLA-A2 protein had been caught in the act of trapping many different peptide antigens within its groove, ready to present to the policing T-cells of the immune system. In effect, the image was a frozen snapshot of a key part of the immune system in action at the molecular level.