The central portion of factor H (modules 10-15) is compact and contains a structurally deviant CCP module

Area of Science:

• Biochemistry
• Structural Biology
• Immunology

Background:

• Complement factor H (fH) regulates the complement system, a key part of innate immunity.
• The N-terminal and C-terminal CCP modules of fH bind C3b and carbohydrates, controlling complement activation.
• The structural and functional roles of the central CCP modules (10-15) are poorly understood, with hypotheses suggesting a flexible tether or a large bend.

Purpose of the Study:

• To elucidate the structural organization and flexibility of the central CCP modules (10-15) of complement factor H (fH).
• To test hypotheses regarding the role of the central fH region as a flexible tether or a large bend.
• To investigate the structural and functional significance of CCP module 13 within fH.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy to determine the structure of fH12-13.
• Analytical ultracentrifugation and X-ray scattering to assess the overall structure and rigidity of central fH modules.

Main Results:

• The NMR structure of fH12-13 revealed an archetypal CCP module 12 and a uniquely short CCP module 13 with a protruding helix and electropositive patch.
• The linker between CCPs 12 and 13 is not flexible and packs between the modules, forming a shallow 'vee' shape.
• Analytical ultracentrifugation and X-ray scattering indicated that the central fH modules (10-15) are compact and rigid, with tilted, zigzagging arrangements, not a smooth bend or flexible tether.

Conclusions:

• The central region of fH (CCPs 10-15) is structurally compact and rigid, refuting models of a flexible tether or smooth bend.
• CCP module 13 exhibits unique structural features and surface charge distribution, suggesting a specialized, non-passive role.
• The central CCP modules of fH likely play an active, structurally specialized role in complement regulation beyond simple scaffolding.