Crystal structures of Bbp from Staphylococcus aureus reveal the ligand binding mechanism with Fibrinogen α

Abstract

Bone sialoprotein-binding protein (Bbp), a MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules) family protein expressed on the surface of Staphylococcus aureus (S. aureus), mediates adherence to fibrinogen α (Fg α), a component in the extracellular matrix of the host cell and is important for infection and pathogenesis. In this study, we solved the crystal structures of apo-Bbp273−598 and Bbp273−598-Fg α561−575 complex at a resolution of 2.03 Å and 1.45 Å, respectively. Apo-Bbp273−598 contained the ligand binding region N2 and N3 domains, both of which followed a DE variant IgG fold characterized by an additional D1 strand in N2 domain and D1′ and D2′ strands in N3 domain. The peptide mapped to the Fg α561−575 bond to Bbp273−598 on the open groove between the N2 and N3 domains. Strikingly, the disordered C-terminus in the apo-form reorganized into a highly-ordered loop and a β-strand G′′ covering the ligand upon ligand binding. BbpAla298–Gly301 in the N2 domain of the Bbp273−598-Fg α561−575 complex, which is a loop in the apo-form, formed a short α-helix to interact tightly with the peptide. In addition, BbpSer547–Gln561 in the N3 domain moved toward the binding groove to make contact directly with the peptide, while BbpAsp338–Gly355 and BbpThr365–Tyr387 in N2 domain shifted their configurations to stabilize the reorganized C-terminus mainly through strong hydrogen bonds. Altogether, our results revealed the molecular basis for Bbp-ligand interaction and advanced our understanding of S. aureus infection process.