Binding of Efb from Staphylococcus aureus to Fibrinogen Blocks Neutrophil Adherence

Center for Infectious and Inflammatory Disease, Institute of Bioscience and Technology, Texas A&M Health Science Center, Houston, Texas 77030, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2011; 286(11):9865-74. DOI: 10.1074/jbc.M110.199687
Source: PubMed


In addition to its pivotal role in hemostasis, fibrinogen (Fg) and provisional fibrin matrices play important roles in inflammation and regulate innate immune responses by interacting with leukocytes. Efb (the extracellular fibrinogen-binding protein) is a secreted Staphylococcus aureus protein that engages host Fg and complement C3. However, the molecular details underlying the Efb-Fg interaction and the biological relevance of this interaction have not been determined. In the present study, we characterize the interaction of Efb with Fg. We demonstrate that the Fg binding activity is located within the intrinsically disordered N-terminal half of Efb (Efb-N) and that the D fragment of Fg is the region that mediates Efb-N binding. More detailed studies of the Efb-N-Fg interactions using ELISA and surface plasmon resonance analyses revealed that Efb-N exhibits a much higher affinity for Fg than typically observed with Fg-binding MSCRAMMs (microbial surface components recognizing adhesive matrix molecules), and data obtained from ELISA analyses using truncated Efb-N constructs demonstrate that Efb-N contains two binding sites located within residues 30-67 and 68-98, respectively. Efb-N inhibits neutrophil adhesion to immobilized Fg by binding to Fg and blocking the interaction of the protein with the leukocyte integrin receptor, α(M)β(2). A motif in the Fg γ chain previously shown to be central to the α(M)β(2) interaction was shown to be functionally distinguishable from the Efb-N binding site, suggesting that the Fg-Efb interaction indirectly impedes Fg engagement by α(M)β(2). Taken together, these studies provide insights into how Efb interacts with Fg and suggest that Efb may support bacterial virulence at least in part by impeding Fg-driven leukocyte adhesion events.

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    • "Such an example of a synergistic mode of interaction exists for the extracellular fibrinogen-binding (Efb) protein expressed by Staphylococcus aureus. A disordered N-terminal region of Efb binds directly to human fibrinogen, while a highly basic globular domain originating from the C-terminal region of the protein binds with high affinity to complement component C3848586. Although each molecular interaction individually contributes to virulence, a ternary fibrinogen-Efb-C3b complex can form, encapsulating the bacteria in a 'fibrinogen-shield', which results in direct inhibition of phagocytosis[87]. "
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