Structural basis for engagement by complement factor H of C3b on a self surface.

Area of Science:

• Biochemistry
• Immunology
• Structural Biology

Background:

• Complement factor H (FH) is a key regulator of the complement system, preventing damage to host tissues.
• FH attenuates C3b molecules on self-surfaces, a critical step in complement regulation.
• C3b proteolysis yields C3d, which retains the thioester domain crucial for surface attachment.

Purpose of the Study:

• To elucidate the atomic-level structure of the C3d-FH19-20 complex.
• To identify glycosaminoglycan-binding residues within factor H module 20.
• To determine the overall structure of factor H bound to C3b and host surfaces.

Main Methods:

• Nuclear Magnetic Resonance (NMR) and X-ray crystallography were employed to study the C3d-FH19-20 complex.
• Site-directed mutagenesis was used to validate structural findings and merge different structural data.
• Small-angle X-ray scattering (SAXS) provided envelopes for various FH fragments (FH1-4, FH8-15, FH15-19).

Main Results:

• Atomic resolution structures of the C3d-FH19-20 complex were determined, detailing interactions.
• Specific residues in FH module 20 responsible for glycosaminoglycan binding were identified.
• A comprehensive model shows factor H adopting a bent-back conformation, binding simultaneously to two sites on C3b and host surface markers.

Conclusions:

• The study provides unprecedented atomic detail of complement factor H's interaction with C3b and host surfaces.
• The identified glycosaminoglycan-binding sites are crucial for FH's localization and regulatory function.
• The bent-back conformation of FH is essential for its simultaneous engagement with C3b and host tissue, ensuring effective complement regulation.