Vic Arcus - InvitrogenTM Award 2003

Conservation and Variation in Superantigen Architecture and Activity

Dr. Vic Arcus

Superantigens are extraordinary proteins. They are secreted by two pathogenic organisms - Staphylococcus aureus and Streptococcus pyogenes and are directly responsible for a range of symptoms associated with Staphylococcal and Streptococcal infections. These symptoms vary, from vomiting and diahorrea, in the case of Staphylococcal food poisoning, to fatal fever and shock in the case of toxic shock syndrome. Superantigens elicit these toxic responses by interfering with the signals between cells associated with the immune system. This interference, in what is normally a very delicate signalling system, causes a massive immune reaction giving rise to these severe symptoms.

We sought to understand the interaction between superantigens and proteins of the human immune system by using X-ray crystallography to determine the 3-dimensional structures of newly discovered superantigens from both Streptococcus and Staphylococcus. In 1998, our collaborators at the Auckland Medical School found several new superantigen sequences in emerging sequence data from the Staphylococcal and Streptococcal genome projects. We determined the structures of two of these new proteins: SMEZ-2 and SPE-H. The structures showed the overall "fold" which is characteristic of superantigens. They also showed, in molecular detail, the binding face by which they were able to bind to human immune proteins. For SMEZ-2, every Streptococcal strain (24 strains in all) showed allelic variation in the SMEZ gene. This led us to the hypothesis that there is strong evolutionary pressure on these proteins to change their surface residues in order to escape immune detection whilst maintaining their function. There is also reciprocal pressure on the immune system to clear these proteins due to their high toxicity.

The superantigen family had more surprises in store as the complete genome sequence of Staphylococcus aureus revealed a pathogenicity island coding for nine new superantigen-like proteins sequentially positioned in the genome. To characterise this new superantigen family we chose two of these proteins and determined their structures. Concurrently, our collaborators showed that these did not behave as typical superantigens but targeted a separate set of immune proteins. This took the variation that we had previously seen to its natural conclusion and the structures of SET-3 and SET-15, provided insights into this new functional variation grafted onto the conserved superantigen architecture.