C1q inhibitor (chondroitin-4-sulfate proteoglycan): structure and function

Area of Science:

• Biochemistry
• Immunology
• Hematology

Background:

• Serum C1q inhibitor (C1q INH) is a proteoglycan with poorly understood mechanisms and roles in disease.
• Its known functions include precipitating C1q and inhibiting hemolytic activity.

Purpose of the Study:

• To elucidate the mechanisms of C1q INH action.
• To identify the component of C1q INH responsible for its inhibitory and anticoagulant activities.
• To explore the role of C1q INH in inflammatory processes and coagulation.

Main Methods:

• Characterization of C1q INH components.
• Assays to determine C1q inhibitory activity.
• Investigation of C1q INH binding sites on C1q.
• Evaluation of C1q INH effects on plasma clotting time.
• Analysis of C1q INH binding to fibrinogen.

Main Results:

• A 30 kDa core protein possesses the primary C1q inhibitory activity.
• C1q INH binds to both the 'heads' (gC1q) and 'tail' (cC1q) of C1q.
• C1q INH moderately activates the classical complement pathway, consuming C2 and C4.
• Binding to C1q is enhanced at low ionic strength but occurs physiologically.
• The 30 kDa core also exhibits potent anticoagulant activity by binding to fibrinogen's E and D domains.
• Binding sites for C1q and fibrinogen on the 30 kDa core are distinct.
• Elevated C1q INH concentrations are found in rheumatoid arthritis and systemic lupus erythematosus.

Conclusions:

• The 30 kDa core protein of C1q INH is crucial for its C1q inhibitory and anticoagulant functions.
• C1q INH's ability to activate complement and affect fibrinogen suggests a role in inflammation, coagulation, and potentially atherogenesis.
• Physiological binding of C1q INH to C1q and fibrinogen highlights its potential involvement in inflammatory microenvironments and tissue repair.