C4b-binding protein: The good, the bad and the deadly. Novel functions of an old friend

Area of Science:

• Immunology
• Complement System Biology
• Glycoprotein Function

Background:

• C4b-binding protein (C4BP) is a major soluble inhibitor of the classical and lectin complement pathways.
• This plasma glycoprotein comprises alpha and beta chains, rich in complement control protein (CCP) domains.
• C4BP is primarily synthesized in the liver, with expression also noted in the lungs and pancreas.

Purpose of the Study:

• To elucidate the multifaceted roles of C4BP beyond its known complement inhibitory functions.
• To investigate C4BP's interactions with apoptotic cells, amyloid structures, and bacterial pathogens.
• To understand the implications of C4BP's diverse functions in various physiological and pathological contexts.

Main Methods:

• Structure-function analysis of C4BP, focusing on CCP domains for complement inhibition.
• Investigation of C4BP binding to apoptotic/necrotic cells via its beta-chain and protein S.
• Studies on C4BP's interaction with amyloid fibrils and its influence on amyloid polypeptide fibrillation.
• Analysis of C4BP interactions with Streptococcus pyogenes and its impact on bacterial survival.

Main Results:

• The alpha-chain's CCP1-3 domains are critical for complement inhibition.
• C4BP binding to apoptotic cells, mediated by protein S, prevents complement-induced inflammation.
• C4BP interacts with amyloid, potentially mitigating pro-inflammatory effects of islet amyloid polypeptide.
• Bacterial pathogens like Streptococcus pyogenes exploit C4BP for immune evasion and enhanced adhesion.

Conclusions:

• C4BP exhibits diverse biological functions, extending beyond complement inhibition.
• Its interactions with cellular debris, amyloid, and pathogens highlight its complex role in host defense and inflammation.
• C4BP can act protectively or detrimentally depending on the specific biological context and interactions.