Hydrodynamic data show that C1- inhibitor of complement forms compact complexes with C1-r and C1-s

Area of Science:

• Immunology
• Biochemistry
• Structural Biology

Background:

• The complement cascade is a critical part of the innate immune system.
• C1-inhibitor (C1-INH) regulates the classical and lectin pathways by inhibiting serine proteases C1-r and C1-s.
• Understanding the structural interactions between C1-INH and its targets is crucial for comprehending complement regulation.

Purpose of the Study:

• To analyze the stoichiometry and structural arrangement of complexes formed between C1-inhibitor, C1-r, and C1-s.
• To elucidate the positioning of C1-inhibitor domains relative to C1-r and C1-s domains using hydrodynamic modeling.

Main Methods:

• Analysis of literature sedimentation coefficients (s°20,w) for C1-INH/C1-r and C1-INH/C1-s complexes.
• Application of frictional ratio analysis and the hydrodynamic sphere approach.
• Integration of a two-domain model for C1-inhibitor with cylindrical hydrodynamic models for C1-r and C1-s.

Main Results:

• Stoichiometric complex formation between C1-inhibitor and both C1-r and C1-s was confirmed.
• Hydrodynamic data indicate a specific spatial arrangement within the complexes.
• The glycosylated N-terminal domain of C1-inhibitor is positioned near the central short consensus repeat domains of C1-r and C1-s.

Conclusions:

• The study provides a structural model for C1-inhibitor complexes with C1-r and C1-s based on hydrodynamic data.
• This positioning suggests a mechanism for C1-inhibitor's regulatory function in the complement cascade.
• The findings contribute to a deeper understanding of the molecular interactions governing complement activation.