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Structure and function of C1 inhibitor
1Division of Immunology, Children's Hospital, Boston, MA.
Insights
C1 inhibitor (C1 INH) regulates complement and kinin systems by inhibiting proteases like C1r, C1s, kallikrein, and factor XII. Its serpin structure ensures effective protease inactivation and maintains system balance.
Area of Science:
- Biochemistry
- Immunology
- Protease Inhibition
Background:
- C1 inhibitor (C1 INH) is a key plasma protease inhibitor.
- It regulates complement and kinin-generating systems.
- C1 INH is the sole plasma inhibitor of C1r and C1s.
Purpose of the Study:
- To elucidate the role and mechanism of C1 inhibitor in regulating plasma systems.
- To understand C1 INH's structural and functional relationship with the serpin family.
Main Methods:
- Analysis of C1 INH sequence homology with serpins.
- Investigation of C1 INH's protease cleavage sites and complex formation.
- Examination of C1 INH's role in C1 complex dissociation and autoactivation prevention.
Main Results:
- C1 INH inactivates C1r, C1s, kallikrein, and factor XII.
- Cleavage occurs at an Arg-Thr bond, forming a stable bimolecular complex.
- C1 INH prevents autoactivation of macromolecular C1 and facilitates C1q interaction.
Conclusions:
- C1 INH is structurally similar to other serpins and maintains inhibitory function.
- It plays a critical role in preventing uncontrolled activation of complement and kinin pathways.
- The inhibitor's structure is crucial for its regulatory function in plasma systems.
Abstract:
C1 inhibitor (C1 INH) is a plasma protease inhibitor that is essential for regulation of activation of the complement and kinin generating systems. It is the only inhibitor of C1r and C1s in plasma, and is responsible for about half of the kallikrein and the majority of plasma factor XII inactivating activity. Based on sequence homology, C1 INH is a member of the serpin family of protease inhibitors and related proteins, and its mechanism of action is identical to those of the other protease inhibitor members of the family. Susceptible proteases cleave C1 INH at an Arg-Thr peptide bond (the P1 and P1'residues) that is 34 amino acid residues from the carboxy terminus of the protein. A stable bimolecular complex then is formed between the larger amino terminal portion of the C1 INH molecule and the protease. C1 INH inactivation of C1r and C1s within activated macromolecular C1 results in dissociation of C1 with release of complexes consisting of two molecules of C1 INH and one molecule each of C1r and C1s. C1q is thus allowed to interact with zymogen C1r and C1s or with C1q receptors. Autoactivation of intact macromolecular C1 is also prevented by C1 INH. The structure of C1 INH is quite similar to other serpin plasma protease inhibitors, and C1 INH appears to retain all the major structural features required for maintaining tertiary structure and inhibitory function.(ABSTRACT TRUNCATED AT 250 WORDS)