Structural basis for surface activation of the classical complement cascade by the short pentraxin C-reactive protein

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Human C-reactive protein (CRP) is a key immune defense pentamer involved in autoimmunity.
• CRP targets autoimmune and cardiovascular diseases, but its mechanism of C1 complex activation is unknown.
• Understanding CRP-C1 interaction is crucial for therapeutic strategies.

Purpose of the Study:

• To determine the structure of CRP bound to C1 complex and phosphocholine (PC) ligands.
• To elucidate the mechanism by which CRP activates the complement system.
• To provide structural basis for CRP-mediated complement regulation in immunity and autoimmunity.

Main Methods:

• Cryoelectron tomography (cryoET) and subtomogram averaging were used to determine the structure.
• Synthetic PC mimotopes were synthesized to create cell-mimetic liposome surfaces for CRP binding.
• Structure-guided mutagenesis of CRP was performed to generate an active complex for structural studies.

Main Results:

• A cryoET structure of CRP bound to PC ligands and the C1 complex was obtained.
• CRP formed unique rectangular platforms from four CRP pentamers, binding four C1 head groups.
• Lateral association residues of CRP were identified, explaining previous mutagenesis data.

Conclusions:

• CRP utilizes a novel rectangular platform mechanism to bind and regulate the C1 complex.
• This mechanism differs from antibody Fc-mediated activation, offering specific control over complement activation.
• These findings provide a mechanistic understanding of CRP's role in innate immunity and autoimmunity.