Evidence for steric regulation of fibrinogen binding to Staphylococcus aureus fibronectin-binding protein A (FnBPA)

Area of Science:

• Microbiology
• Structural Biology
• Biochemistry

Background:

• Fn-binding protein A (FnBPA) from Staphylococcus aureus mediates infection initiation and persistence.
• FnBPA possesses adjacent fibrinogen (Fg) and fibronectin (Fn) binding sites.
• Understanding these interactions is crucial for developing anti-infective strategies.

Purpose of the Study:

• To determine the structure of FnBPA's N2N3 domains, including the Fg-binding site.
• To elucidate the mechanism of Fg binding to FnBPA.
• To investigate the interplay between Fg and Fn binding to FnBPA.

Main Methods:

• X-ray crystallography was used to solve the structure of FnBPA N2N3 domains.
• Structures were determined in both apo form and complex with a Fg peptide.
• Biochemical assays were performed to assess Fg and Fn binding.

Main Results:

• The structure of FnBPA N2N3 domains in complex with Fg peptide was resolved.
• Fg binding mechanism is conserved but lacks "latch" strand requirement.
• Fg and N-terminal Fn binding sites are proximal but non-overlapping.
• Intact Fn binding inhibits Fg binding, indicating steric regulation.

Conclusions:

• FnBPA's Fg-binding mechanism is distinct from homologous proteins.
• Steric hindrance by intact Fn regulates Fg binding.
• This interaction mechanism may target Staphylococcus aureus to fibrin-rich thrombi or elastin-rich tissues in vivo.