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J. Biol. Chem., Vol. 282, Issue 35, 25893-25902, August 31, 2007

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The Tandem -Zipper Model Defines High Affinity Fibronectin-binding Repeats within Staphylococcus aureus FnBPA^*

Nicola A. G. Meenan, Livia Visai^¶, Viviana Valtulina, Ulrich Schwarz-Linek^||, Nicole C. Norris, Sivashankarappa Gurusiddappa^**, Magnus Höök^**1, Pietro Speziale², and Jennifer R. Potts³

From the Department of Biology, University of York, P.O. Box 373, York YO10 5YW, United Kingdom, the Department of Biochemistry, University of Pavia, Viale Taramelli 3/B 27100 Pavia, Italy, ^¶Centro di Ingegneria Tissutale, University of Pavia, Viale Taramelli 3/B 27100 Pavia, Italy, the ^||Centre for Biomolecular Sciences, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, United Kingdom, the ^**Center for Extracellular Matrix Biology, Institute of Biosciences and Technology, Texas A & M University System Health Science Center, Houston, Texas 77030-3303, and the Department of Chemistry, University of York, York YO10 5DD, United Kingdom

Binding of the fibronectin-binding protein FnBPA from Staphylococcus aureus to the human protein fibronectin has previously been implicated in the development of infective endocarditis, specifically in the processes of platelet activation and invasion of the endothelium. We recently proposed a model for binding of fibronectin to FnBPA in which the bacterial protein contains 11 potential binding sites (FnBPA-1 to FnBPA-11), each composed of motifs that bind to consecutive fibronectin type 1 modules in the N-terminal domain of fibronectin. Here we show that six of the 11 sites bind with dissociation constants in the nanomolar range; other sites bind more weakly. The high affinity binding sites include FnBPA-1, the sequence of which had previously been thought to be encompassed by the fibrinogen-binding A domain of FnBPA. Both the number and sequence conservation of the type-1 module binding motifs appears to be important for high affinity binding. The in vivo relevance of the in vitro binding studies is confirmed by the presence of antibodies in patients with S. aureus infections that specifically recognize complexes of these six high affinity repeats with fibronectin.

Received for publication, April 11, 2007 , and in revised form, June 15, 2007.

^* This work was supported by the Italian Ministero dell'Istruzione, dell'Università e della Ricerca, IDEE PROGETTUALI (Grandi Programmi Strategici, Decreto Ministeriale 24695, Protocollo RBIPO6FH7J) (to L. V.), Fondazione CARIPLO (2003 1640/10.8485), Fondo di Ateneo per la Ricerca (Pavia, Italy), and PRIN 2001 (Prot. 20011061977_004) (to P. S.). 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 Tables 1 and 2.

¹ Supported by National Institutes of Health Grant AI020624.

² To whom correspondence may be addressed. Tel.: 39-0382-987787; Fax: 39-0382-423108; E-mail: pspeziale{at}unipv.it.

³ Supported by the British Heart Foundation and the Wellcome Trust. To whom correspondence may be addressed: Dept. of Biology, University of York, P.O. Box 373, York YO10 5YW, United Kingdom. Tel.: 44-1904-328679; Fax: 44-1904-328825; E-mail: jp516{at}york.ac.uk.

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