Unravelling protein-protein interactions between complement factor H and C-reactive protein using a multidisciplinary...

Area of Science:

• Immunology
• Biochemistry
• Structural Biology

Background:

• Innate immunity relies on weak protein-protein interactions, particularly within the complement system.
• Dysregulation of complement pathways, involving proteins like complement factor H (CFH), can lead to disease.
• The multivalency of CFH complicates the analysis of its interactions with ligands.

Purpose of the Study:

• To investigate the weak interactions between complement proteins, specifically CFH and its ligand CRP.
• To elucidate the structural basis of CFH self-association and its interaction with CRP.
• To understand the role of these interactions in age-related macular degeneration.

Main Methods:

• Synchrotron X-ray solution scattering and constrained modeling to determine CFH structure and self-association.
• Analytical ultracentrifugation (AUC) to identify CFH multimer formation with metal ions.
• Surface plasmon resonance (SPR) combined with X-ray and AUC to study CRP self-association and CFH-CRP binding.

Main Results:

• Determined the solution structure and self-associative properties of CFH.
• Identified zinc-mediated formation of larger CFH multimers.
• Revealed that C-reactive protein (CRP) self-associates and binds to CFH at two distinct sites.

Conclusions:

• Weak interactions are critical for complement system function and regulation.
• CFH exhibits complex self-association and multimerization.
• The dual-site binding of CRP to CFH provides insights into its role in age-related macular degeneration pathogenesis.