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How the Streptococcal M87 Protein Binds Human C4b-Binding Protein



How the Streptococcal M87 Protein Binds Human C4b-Binding Protein


Matthew Allen McGowan

Master of Science

University of California, San Diego, 2017

Professor Partho Ghosh, Chair

The pathogenic bacterium Streptococcus pyogenes, or Group A Streptococcus (GAS), causes diseases throughout world. These diseases can range from mild to life threatening and leave the afflicted individuals susceptible to autoimmune response. Despite the widespread threat of GAS, no vaccine exists against it. The lack of a vaccine is due in large part to the antigenic variability of the N terminus, or hyper variable region (HVR), of the GAS surface protein known as the M protein.

One promising approach to vaccine design studies the interactions between the human complement inhibitor C4b-binding protein (C4BP) and the M protein, as C4BP recognizes many strains of GAS at the HVR. Four crystal structures of M protein HVRs in complex with the binding domains of C4BP (C4BPα1-2) were recently determined, revealing conserved binding patterns between M proteins and C4BP that could be applied to about half of the GAS strains shown to bind C4BP.

To build the current understanding of this interaction, eight M protein HVRs whose sequences did not match the previous binding motifs (M14.5HVR, M18.6 HVR, M58 HVR, M80 HVR, M75 HVR, M87 HVR, M112HVR, PrtHHVR) were cloned, expressed, and purified to obtain co-crystal complexes with C4BPα1-2. The 2.69 Å resolution limit structure of the M87HVR-C4BPα1-2 complex was determined. The interactions between M87HVR and C4BPα1-2 has further demonstrated the involvement of key binding residues on C4BP and has also identified unique residue interactions. A similar binding pattern can be applied to other strains, giving further insight into the potential design of a broadly recognizing GAS vaccine.

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