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J. Biol. Chem., Vol. 283, Issue 1, 638-647, January 4, 2008

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Evidence for the "Dock, Lock, and Latch" Ligand Binding Mechanism of the Staphylococcal Microbial Surface Component Recognizing Adhesive Matrix Molecules (MSCRAMM) SdrG^*

M. Gabriela Bowden¹, Alejandro P. Heuck^¶, Karthe Ponnuraj^||**, Elena Kolosova, Damon Choe, Sivashankarappa Gurusiddappa, Sthanam V. L. Narayana^||, Arthur E. Johnson^¶, and Magnus Höök

From the Center for Extracellular Matrix Biology, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030, the Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Massachusetts 01003, the ^¶Department of Molecular and Cellular Medicine, School of Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843, the ^||Center for Biophysical Sciences and Engineering, University of Alabama, Birmingham, Alabama 35294, and the ^**Center of Advanced Study in Crystallography and Biophysics, University of Madras, Chennai 600025, India

Staphylococcus epidermidis is an opportunistic pathogen and a major cause of foreign body infections. The S. epidermidis fibrinogen (Fg)-binding adhesin SdrG is necessary and sufficient for the attachment of this pathogen to Fg-coated materials. Based largely on structural analyses of the ligand binding domain of SdrG as an apo-protein and in complex with a Fg-like peptide, we proposed that SdrG follows a "dock, lock, and latch" mechanism to bind to Fg. This binding mechanism involves the docking of the ligand in a pocket formed between two SdrG subdomains followed by the movement of a C-terminal extension of one subdomain to cover the ligand and to insert and complement a β-sheet in a neighboring subdomain. These proposed events result in a greatly stabilized closed conformation of the MSCRAMM-ligand complex. In this report, we describe a biochemical analysis of the proposed conformational changes that SdrG undergoes upon binding to its ligand. We have introduced disulfide bonds into SdrG to stabilize the open and closed forms of the apo-form of the MSCRAMM. We show that the stabilized closed form does not bind to the ligand and that binding can be restored in the presence of reducing agents such as dithiothreitol. We have also used Förster resonance energy transfer to dynamically show the conformational changes of SdrG upon binding to its ligand. Finally, we have used isothermic calorimetry to determine that hydrophobic interactions between the ligand and the protein are responsible for re-directing the C-terminal extension of the second subdomain required for triggering the β-strand complementation event.

Received for publication, July 30, 2007 , and in revised form, October 29, 2007.

^* This work was supported by National Institutes of Health Grants AI61426 (to M. G. B.), AI020624 (to M. H.), and GM26494 (to A. E. J.) and Chair Grant BE-0017 from the Robert A. Welch Foundation (to A. E. J.). 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 To whom correspondence should be addressed: 2121 W. Holcombe Blvd., Houston TX 77030-3303. Tel.: 713-677-7572; Fax: 713-677-7576; E-mail: gbowden{at}ibt.tamhsc.edu.

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