Molecular Interactions between Complement Factor H and Its Heparin and Heparan Sulfate Ligands

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• Complement factor H (CFH) is crucial for regulating the alternative complement pathway.
• Heparan sulfate (HS) on cell surfaces plays a role in CFH-mediated complement regulation.
• Understanding the molecular interactions of CFH with HS is key to elucidating complement activation mechanisms.

Purpose of the Study:

• To determine the solution structures of heparin and desulfated HS.
• To characterize the binding interaction between CFH and HS.
• To propose a molecular model for CFH binding to cell surfaces.

Main Methods:

• Solution structural studies using scattering and ultracentrifugation.
• Analysis of HS and heparin oligosaccharide structures.
• Determination of CFH domain structure.
• Binding studies using CFH fragments and heparin-coated sensor chips.

Main Results:

• HS and heparin exhibit distinct solution structures with varying flexibility.
• CFH binds preferentially to the sulfated S-regions of HS over NA-regions.
• A two-site, co-operative binding model for CFH interaction with cell surface HS was identified.
• Moderate binding affinities (micromolar dissociation constants) were observed for CFH-heparin and CFH-C3b interactions.

Conclusions:

• CFH interacts with cell surface HS via a two-site mechanism, influencing its interaction with C3b.
• Defects in either CFH-heparin binding site can impair complement regulation and lead to immune disorders.
• This study provides molecular insights into the role of CFH-HS interactions in maintaining immune homeostasis.