Research article summary (published 6 Sep 2009):

Complement component C2, inhibiting a latent serine protease in the classical pathway of complement activation.

Full Abstract

The innate immune response to infection or injury involves an antigen-antibody triggered classical pathway (CP) of complement activation, in which soluble and cell surface plasma proteins cooperatively effect elimination of foreign organisms and damaged host cells. However, protracted or dysfunctional complement activation can lead to inflammatory diseases. Complement component 2 bound to C4b is cleaved by classical (C1s) or lectin (MASP2) proteases to produce C4bC2a, a very short-lived C3 convertase (t(1/2) 2 min) that in turn cleaves C3 to C3a and C3b, leading ultimately to formation of Membrane Attack Complex (MAC) and lysis of bacteria and damaged cells. C2 has the same serine protease domain as C4bC2a but in an inactive zymogen-like conformation, requiring cofactor-induced conformational change for activity. Here, we show that C2 has catalytic protease activity in its own right above pH 7, in the absence of cofactor, processing C3 and C3-derived chromogenic peptide fragments. In contrast to the instability of C3 convertase (t(1/2) 2 min, pH 7), the C2 enzyme is indefinitely stable under alkaline conditions, facilitating studies of its catalytic properties and development of small molecule inhibitors. We characterize the catalytic activity of C2 against C3 and short paranitroanilide peptide substrates, and identify potent small molecule inhibitors of C2 that also inhibit classical pathway C3 convertase, MAC formation, and hemolysis of sensitized sheep erythrocytes. These results provide a new avenue and valuable new insights to inhibiting CP complement activation relevant to inflammatory diseases.

Author information

Author/s: Halili, Maria A (MA); Ruiz-Gómez, Gloria (G); Le, Giang T (GT); Abbenante, Giovanni (G); Fairlie, David P (DP);

Affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Biochemistry (Biochemistry), published in United States. (Language: eng)

Reference: 2009-Sep; vol 48 (issue 35) : pp 8466-72

Dates: Created 2009/09/01; Completed 2009/09/25;

PMID: 19642650, status: MEDLINE (last retrieval date: 9/25/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Complement Activation Complement C2 - chemistry; pharmacology Complement C2b - metabolism Complement C3 - metabolism Complement C3-C5 Convertases - antagonists & inhibitors; metabolism Complement C3b - metabolism Complement C4b - metabolism Complement Membrane Attack Complex

Complement Membrane Attack Complex Complement Pathway, Classical Erythrocytes Humans Hydrogen-Ion Concentration Protein Conformation Protein Folding Serine Endopeptidases - drug effects; metabolism Sheep

Associated Chemicals: Complement C2 (0) ; Complement C2b (0) ; Complement C3 (0) ; Complement Membrane Attack Complex (0) ; Complement C3b (80295-43-8) ; Complement C4b (80295-50-7) ; Complement C3-C5 Convertases (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)

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