Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• The complement system tags pathogens and cellular debris for removal.
• Cleavage of C3b by factor I (FI) is crucial for regulating immune responses and preventing self-damage.
• The precise mechanism by which FI, with cofactor assistance, cleaves C3b remains incompletely understood.

Purpose of the Study:

• To elucidate the structural basis for factor I-mediated cleavage of C3b.
• To understand how regulators like factor H influence FI activity on C3b.
• To explain the generation of distinct C3b degradation products.

Main Methods:

• X-ray crystallography of C3b in complex with factor I and factor H domains.
• Structural analysis of C3b-FI-FH complexes.
• Biochemical assays to assess cleavage and regulator binding.

Main Results:

• The crystal structure reveals how FI binds C3b in complex with FH, positioning its catalytic site.
• FI binding stabilizes C3b for proteolysis, with FH acting as a cofactor.
• Differential unfolding of C3b domains upon one versus two cleavages explains the generation of iC3b and C3dg.

Conclusions:

• FI generates distinct C3b opsonins (iC3b, C3dg) through context-dependent cleavage.
• Structural insights reveal the mechanism of C3b regulation by FI and FH.
• This explains how the complement system distinguishes between foreign, danger, and self signals.