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Superantigens

Superantigens are molecules that stimulate, independent of antigen, those T- cells displaying a particular beta chain variable region (Vbeta) of the T-cell receptor. These molecules are the most powerful T-cell mitogens known inducing biological effects at femtomolar concentrations. Recently it has been demonstrated that superantigens possess biological properties, e.g., lethality and emesis, which are separable from their T-cell mitogenicity. Studies have implicated superantigens in such diseases as food poisoning, toxic shock syndrome, scarlet and rheumatic fever, arthritis, multiple sclerosis, diabetes, sudden infant death syndrome, Kawasaki syndrome (a leading cause of acquired heart defects), and AIDS.

The best characterized superantigens are the microbial toxins from Staphylococcus aureus and Streptococcus pyogenes. The Ohlendorf lab has studied two staphylococcal superantigens - Toxic Shock Syndrome Toxin-1 (TSST-1) and Exfoliative Toxin A (ETA).

Schematic representation of the secondary structural elements of the ETA molecule.

The staphylococcal toxin, toxic shock syndrome toxin-1 (TSST-1), is the principal causative agent of toxic shock syndrome. The Ohlendorf lab has determined the structure of TSST-1 in three crystal forms. The resulting structure is shown below. The structures of six TSST-1 mutants with alternate biologically properties have also been determined. In five of these mutants the changes involve surface residues and result in minimal structural changes. However in the Q136A the loop behind the long central alpha helix rearranges. Since this mutant abolishes lethality with only small reductions in superantigenicity, this loop is important in controlling lethality of the toxin.

Work on TSST-1 is in collaboration with Dr. Patrick Schlievert of the Department of Microbiology

This figure depicts the secondary structural elements of the TSST-1 molecule. a helices are shown as magenta ribbons, while sections of β sheet are shown as yellow ribbons.

Selected Publications

• Earhart, C. A., D. T. Mitchell, et al. (1998). "Structures of five mutants of toxic shock syndrome toxin-1 with reduced biological activity." Biochemistry 37(20): 7194-202.
• Prasad, G. S., R. Radhakrishnan, et al. (1997). "Refined structures of three crystal forms of toxic shock syndrome toxin- 1 and of a tetramutant with reduced activity." Protein Sci 6(6): 1220-7.
• Murray, D. L., C. A. Earhart, et al. (1996). "Localization of biologically important regions on toxic shock syndrome toxin 1." Infect Immun 64(1): 371-4.
• Earhart, C. A., G. S. Prasad, et al. (1993). "Growth and analysis of crystal forms of toxic shock syndrome toxin 1." Proteins 17(3): 329-34.

Exfoliative Toxin A

Exfoliative toxin A (ETA) is the principal causative agent in staphylococcal scalded skin syndrome (SSSS). SSSS is a typically nonfatal disease of newborns and is characterized by a specific intraepidermal separation of layers of the skin. The Ohlendorf lab has determined the structure of ETA in several crystal forms. The resulting structure is shown below. The structure of ETA is unlike that of any other superantigen. Indeed, its structure indicates that ETA is a serine protease with several novel properties including:

Work on TSST-1 is in collaboration with Dr. Patrick Schlievert of the Department of Microbiology and Dr. Gregory Bohach, Department of Microbiology, Molecular Biology and Biochemistry at the University of Idaho.

Selected Publications

• Vath, G. M., C. A. Earhart, et al. (1997). "The structure of the superantigen exfoliative toxin A suggests a novel regulation as a serine protease." Biochemistry 36(7): 1559-66.