title: Electrostatic contributions drive the interaction between Staphylococcus aureus protein Efb-C and its complement target C3d.
abstract: 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 subdomain 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 and 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.
authors.affiliation: Department of Computer Science, Rice University, Houston, Texas 77005, USA.
authors.forename: Nurit
authors.initials: N
authors.lastname: Haspel
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.forename: Brian V
authors.initials: BV
authors.lastname: Geisbrecht
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Kavraki
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D015933:Complement C3d / Q000737:chemistry* / Q000276:immunology; D019295:Computational Biology; D003460:Crystallization; D006801:Humans; D006860:Hydrogen Bonding; D017354:Point Mutation; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology*; D055672:Static Electricity; D013816:Thermodynamics; D014961:X-Ray Diffraction
chemical_list: D001426:Bacterial Proteins; C114014:Efb protein, Staphylococcus aureus; D011994:Recombinant Proteins; D015933:Complement C3d