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J. Biol. Chem., Vol. 281, Issue 6, 3217-3226, February 10, 2006

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Divergence in the Plasminogen-binding Group A Streptococcal M Protein Family

FUNCTIONAL CONSERVATION OF BINDING SITE AND POTENTIAL ROLE FOR IMMUNE SELECTION OF VARIANTS^*

Martina Sanderson-Smith¹, Michael Batzloff, Kabada S. Sriprakash, Mark Dowton, Marie Ranson, and Mark J. Walker²

From the School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522 and Queensland Institute for Medical Research, Herston, Queensland 4006, Australia

Group A streptococci (GAS) display receptors for the human zymogen plasminogen on the cell surface, one of which is the plasminogen-binding group A streptococcal M protein (PAM). Characterization of PAM genes from 12 GAS isolates showed significant variation within the plasminogen-binding repeat motifs (a1/a2) of this protein. To determine the impact of sequence variation on protein function, recombinant proteins representing five naturally occurring variants of PAM, together with a recombinant M1 protein, were expressed and purified. Equilibrium dissociation constants for the interaction of PAM variants with biotinylated Glu-plasminogen ranged from 1.58 to 4.99 nM. Effective concentrations of prototype PAM required for 50% inhibition of plasminogen binding to immobilized PAM variants ranged from 0.68 to 22.06 nM. These results suggest that although variation in the a1/a2 region of the PAM protein does affect the comparative affinity of PAM variants, the functional capacity to bind plasminogen is conserved. Additionally, a potential role for the a1 region of PAM in eliciting a protective immune response was investigated by using a mouse model for GAS infection. The a1 region of PAM was found to protect immunized mice challenged with a PAM-positive GAS strain. These data suggest a link between selective immune pressure against the plasminogen-binding repeats and the functional conservation of the binding domain in PAM variants.

Received for publication, August 9, 2005 , and in revised form, November 23, 2005.

^* This work was supported in part by National Health and Medical Research Council Grant 303401. 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.

¹ Recipient of an Australian Research Council postgraduate award.

² To whom correspondence should be addressed: School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia. Tel.: 61-2-4221-3439; Fax: 61-2-4221-4135; E-mail: mwalker{at}uow.edu.au.

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