Insights into complement convertase formation based on the structure of the factor B-cobra venom factor complex

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• The complement system is crucial for immune protection, relying on C3 convertases assembled on pathogen surfaces.
• Pro-convertases, like C3b and factor B (FB), are precursors to these essential protease complexes.

Purpose of the Study:

• To elucidate the structural mechanisms of pro-convertase formation involving human factor B (FB) and cobra venom factor (CVF).
• To understand the molecular interactions governing the assembly and specificity of complement convertases.

Main Methods:

• X-ray crystallography (2.2-A resolution) of the FB-CVF pro-convertase.
• Small-angle X-ray scattering (SAXS).
• Electron microscopy (EM).

Main Results:

• Detailed structure of the FB-CVF pro-convertase, revealing specific contacts for FB loading via its Ba segment.
• Identified binding interactions between the Bb protease segment and CVF's C-terminus.
• Proposed a dynamic equilibrium model explaining structural differences between CVFB and C3bB complexes.

Conclusions:

• Structural insights into FB binding to CVF explain specificity for homologous C3b over other complement components.
• Understanding pro-convertase dynamics provides a foundation for developing novel complement-targeted therapeutics.