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J. Biol. Chem., Vol. 281, Issue 46, 35281-35288, November 17, 2006

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Streptococcal Mitogenic Exotoxin, SmeZ, Is the Most Susceptible M1T1 Streptococcal Superantigen to Degradation by the Streptococcal Cysteine Protease, SpeB^*

Mohammed M. Nooh^¶1, Ramy K. Aziz^¶12, Malak Kotb^¶, Alexey Eroshkin^||, Woei-Jer Chuang^**, Thomas Proft, and Rita Kansal^¶3

From the Departments of Molecular Sciences and Surgery, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and the ^¶Research Center, the Veterans Affairs Medical Center, Memphis, Tennessee 38104, ^||the Burnham Institute, La Jolla, California 92037, the ^**Department of Biochemistry, National Cheng Kung University College of Medicine, Tainan 701, Taiwan, and the Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Superantigens (SAgs) play an important role in the pathogenesis of severe invasive infections caused by Group A Streptococcus (GAS). We had shown earlier that the expression of streptococcal cysteine protease SpeB results in partial loss of the immune-stimulating activity of the native secreted GAS SAgs, namely the streptococcal pyrogenic exotoxins produced by the globally disseminated M1T1 GAS strain, associated with invasive infections worldwide. In this study, we examined the susceptibility of each of the M1T1 recombinant SAgs to degradation by rSpeB. Whereas SmeZ was degraded completely within 30 min of incubation with rSpeB, SpeG, and SpeA were more resistant and SpeJ was completely unaffected by the proteolytic effects of this protease. Proteomic analyses demonstrated that the order of susceptibility of the M1T1 SAgs to SpeB proteolysis is unaltered when they are present in a mixture that reflects their native physiological status. As expected, the degradation of SmeZ abolished its immune stimulatory activity. In silico sequence disorder and structural analyses revealed that SmeZ, unlike the three other structurally related SAgs, possesses a putative SpeB cleavage site within an area of the protein likely to be exposed to the surface. The study provides evidence for the effect of subtle structural differences between highly similar SAgs on their biological activity.

Received for publication, June 9, 2006 , and in revised form, August 21, 2006.

^* This work was supported in part by the American Heart Association Grant GIA-0455280B (to R. K.), Grant AI40198-06 from NIAID, National Institutes of Health (to M. K.), and by the Research and Development Office, Medical Research Service, Dept. of Veterans Affairs Merit Award (to M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ These individuals contributed equally to this work.

² Present address: Dept. of Microbiology and Immunology, Faculty of Pharmacy, Cairo University.

³ To whom correspondence should be addressed: The Veterans Affairs Medical Center, 1030 Jefferson Ave., 151 Research Services, Memphis, TN 38104. Tel.: 901-523-8990 (ext. 7609); Fax: 901-577-7273; E-mail: rkansal{at}utmem.edu.

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