7S0R

Crystal Structure of a Complement Factor H-binding Fragment within the B75KN Region of the Group B Streptococcus Beta Antigen C Protein

Summary for 7S0R

• Entry DOI: 10.2210/pdb7s0r/pdb
• Descriptor: C protein beta antigen (1 entity in total)
• Functional Keywords: cell-surface protein, immune evasion, complement, factor h, protein binding
• Biological source: Streptococcus agalactiae
• Total number of polymer chains: 2
• Total formula weight: 24194.30

Authors

Xu, X.,Geisbrecht, B.V. (deposition date: 2021-08-31, release date: 2021-12-15, Last modification date: 2024-11-13)

Primary citation

Xu, X.,Lewis Marffy, A.L.,Keightley, A.,McCarthy, A.J.,Geisbrecht, B.V.
Group B Streptococcus Surface Protein beta : Structural Characterization of a Complement Factor H-Binding Motif and Its Contribution to Immune Evasion.
J Immunol., 208:1232-1247, 2022

PubMed Abstract: The β protein from group B (GBS) is a ∼132-kDa, cell-surface exposed molecule that binds to multiple host-derived ligands, including complement factor H (FH). Many details regarding this interaction and its significance to immune evasion by GBS remain unclear. In this study, we identified a three-helix bundle domain within the C-terminal half of the B75KN region of β as the major FH-binding determinant and determined its crystal structure at 2.5 Å resolution. Analysis of this structure suggested a role in FH binding for a loop region connecting helices α1 and α2, which we confirmed by mutagenesis and direct binding studies. Using a combination of protein cross-linking and mass spectrometry, we observed that B75KN bound to complement control protein (CCP)3 and CCP4 domains of FH. Although this binding site lies within a complement regulatory region of FH, we determined that FH bound by β retained its decay acceleration and cofactor activities. Heterologous expression of β by resulted in recruitment of FH to the bacterial surface and a significant reduction of C3b deposition following exposure to human serum. Surprisingly, we found that FH binding by β was not required for bacterial resistance to phagocytosis by neutrophils or killing of bacteria by whole human blood. However, loss of the B75KN region significantly diminished bacterial survival in both assays. Although our results show that FH recruited to the bacterial surface through a high-affinity interaction maintains key complement-regulatory functions, they raise questions about the importance of FH binding to immune evasion by GBS as a whole.

PubMed: 35110419
DOI: 10.4049/jimmunol.2101078

Experimental method

X-RAY DIFFRACTION (2.5 Å)