Distal recognition site for classical pathway convertase located in the C345C/netrin module of complement component
A Sandoval1, R Ai, J M Ostresh
1Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|July 6, 2000
Summary
Researchers identified a novel binding site on complement component 5 (C5) critical for classical pathway (CP) activation. This KYNFSF sequence is essential for CP convertase activity but not for cobra venom factor (CVF) convertase.
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Previous studies identified potential protein-protein interaction sites in complement C3 and C5.
- Indels in the complement C345 protein family provided initial clues to these interaction sites.
Purpose of the Study:
- To investigate a specific protein-protein interaction site near the C terminus of the C5 alpha-chain.
- To determine the role of the KYNFSF sequence in complement C5 convertase activity.
Main Methods:
- Alanine-scanning mutagenesis was performed on 16 residues within the KEALQIKYNFSF RYIYPLD sequence of C5.
- Mutant C5 activities were assessed for classical pathway (CP) and cobra venom factor (CVF)-dependent convertase activation.
- A synthetic peptide corresponding to the KYNFSF sequence was used to validate findings.
Main Results:
- Alanine substitutions in the KYNFSF sequence significantly reduced C5 activity, with K, Y, and F residues having the most pronounced effects.
- Mutants with reduced activity were resistant to CP C5 convertase but showed normal susceptibility to CVF-dependent convertase.
- The synthetic peptide mimicked these effects, inhibiting CP but not CVF convertase activation.
Conclusions:
- The KYNFSF sequence represents a novel, distal binding site for the classical pathway (CP) C5 convertase.
- This binding site is specific to CP activation and is not involved in CVF-dependent convertase activity.
- The identified module (C345C/NTR) containing this site is found in various proteins, suggesting broader functional relevance.
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