Evidence for Steric Regulation of Fibrinogen binding to Staphylococcus aureus fibronectin-binding protein A (FnBPA).

TY - JOUR

T1 - Evidence for Steric Regulation of Fibrinogen binding to Staphylococcus aureus fibronectin-binding protein A (FnBPA).

AU - Stemberk, Vaclav

AU - Jones, Richard Paul Owen

AU - Moroz, Olga

AU - Atkin, Kate Elizabeth

AU - Edwards, Andrew M.

AU - Turkenburg, Johan P.

AU - Leech, Andrew P.

AU - Massey, Ruth C.

AU - Potts, Jennifer R.

PY - 2014/5/2

Y1 - 2014/5/2

N2 - The adjacent fibrinogen (Fg)- and fibronectin (Fn)- binding sites on Fn-binding protein A (FnBPA), a cell-surface protein from Staphylococcus aureus, are implicated in the initiation and persistence of infection. FnBPA contains a single Fg-binding site (that also binds elastin) and multiple Fn-binding sites. Here, we solved the structure of the N2N3 domains containing the Fg-binding site of FnBPA in the apo-form and in complex with a Fg-peptide. The Fg-binding mechanism is similar to that of homologous bacterial proteins but without the requirement for latch strand residues. We show that the Fg- and the most N-terminal Fn-binding sites are non-overlapping but in close proximity. While Fg and a sub-domain of Fn can form a ternary complex on an FnBPA protein construct containing a Fg- and single Fn-binding site, binding of intact Fn appears to inhibit Fg binding, suggesting steric regulation. Given the concentrations of Fn and Fg in the plasma, this mechanism might result in targeting of S. aureus to fibrin-rich thrombi or elastin-rich tissues.

AB - The adjacent fibrinogen (Fg)- and fibronectin (Fn)- binding sites on Fn-binding protein A (FnBPA), a cell-surface protein from Staphylococcus aureus, are implicated in the initiation and persistence of infection. FnBPA contains a single Fg-binding site (that also binds elastin) and multiple Fn-binding sites. Here, we solved the structure of the N2N3 domains containing the Fg-binding site of FnBPA in the apo-form and in complex with a Fg-peptide. The Fg-binding mechanism is similar to that of homologous bacterial proteins but without the requirement for latch strand residues. We show that the Fg- and the most N-terminal Fn-binding sites are non-overlapping but in close proximity. While Fg and a sub-domain of Fn can form a ternary complex on an FnBPA protein construct containing a Fg- and single Fn-binding site, binding of intact Fn appears to inhibit Fg binding, suggesting steric regulation. Given the concentrations of Fn and Fg in the plasma, this mechanism might result in targeting of S. aureus to fibrin-rich thrombi or elastin-rich tissues.

KW - Fibrinogen

KW - Fibronectin

KW - Isothermal titration calorimetry

KW - Staphylococcus aureus

KW - Surface Plasmon Resonance (SPR)

KW - X-ray crystallography

KW - FnBPA

U2 - 10.1074/jbc.M113.543546

DO - 10.1074/jbc.M113.543546

M3 - Article

SN - 0021-9258

VL - 289

SP - 12842

EP - 12851

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 18

ER -