Solution Structures of Complement C2 and Its C4 Complexes Propose Pathway-specific Mechanisms for Control and...

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• The complement system comprises three main activation pathways: lectin (LP), classical (CP), and alternative.
• LP and CP pathways initiate via distinct molecular patterns and share downstream steps involving C4, C2, and C3.
• Understanding the structural basis of these pathways is crucial for immune response modulation.

Purpose of the Study:

• To elucidate the solution structures of key complement complexes: C3 proconvertase and C3 convertase.
• To compare the activation mechanisms of LP/CP pathways with the alternative pathway.

Main Methods:

• Small angle X-ray scattering (SAXS) analysis was employed to determine the structures of C3 proconvertase, C3 convertase, and unbound C2.
• Studies included both native and deglycosylated forms of C4b2 and C2 to assess glycan influence.

Main Results:

• Structural models derived from SAXS were independent of glycan modifications.
• SAXS models indicate a different activation mode for CP/LP C3 proconvertase compared to the alternative pathway's C3bB proconvertase.
• The active CP/LP C3 convertase (C4b2a) exhibits structural similarity to the alternative pathway's C3 convertase (C3bBb).

Conclusions:

• The structural data suggest distinct activation mechanisms for CP/LP and alternative pathway proconvertases, likely due to differing protease properties.
• The conserved structure of C3 convertases across pathways aligns with their shared function in cleaving C3 and C5.
• These findings provide insights into complement system activation and regulation.