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Published online before print August 7, 2008
Protein Science, DOI: 10.1110/ps.036624.108
 Copyright © 2008 The Protein Society
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Electrostatic Contributions Drive the Interaction Between Staphylococcus aureus Protein Efb-C and its Complement Target C3d

Nurit Haspel1, Daniel Ricklin2, Brian V Geisbrecht3, Lydia E. Kavraki1, and John D. Lambris2,4

1 Rice University;
2 University of Pennsylvania;
3 University of Missouri-Kansas City

(RECEIVED May 29, 2008; ACCEPTED July 28, 2008)

The C3-inhibitory domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb-C) defines a novel three-helix bundle motif that regulates complement activation. Previous crystallographic studies of Efb-C bound to its cognate sub-domain of human C3 (C3d) identified Arg-131 and Asn-138 of Efb-C as key residues for its activity. In order to characterize more completely the physical and chemical driving forces behind this important interaction, we employed in this study a combination of structural, biophysical, and computational methods to analyze the interaction of C3d with Efb-C and the single point mutants R131A and N138A. Our results show that while these mutations do not drastically affect the structure of the Efb-C/C3d recognition complex, they have significant adverse effects on both the thermodynamic kinetic profiles of the resulting complexes. We also characterized other key interactions along the Efb-C/C3d binding interface and found an intricate network of salt bridges and hydrogen bonds that anchor Efb-C to C3d, resulting in its potent complement inhibitory properties.

Keywords: Proteins of the Immune System; Structure; Computational Analysis of Protein Structure; Molecular mechanics/dynamics; Thermodynamics, Hydrodynamics; Complement; Efb-C; Electrostatics; Protein-protein Interaction

4 E-mail: lambris{at}mail.med.upenn.edu


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