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The reaction mechanism of the internal thioester in the human complement component C4

Nature volume 379, pages 177–179 (1996)Cite this article

Abstract

A KEY step in the elimination of pathogens from the body is the covalent binding of complement proteins C3 and C4 to their surfaces1–5. Proteolytic activation of these proteins results in a conformational change6,7, and an internal thioester8–10 is exposed which reacts with amino or hydroxyl groups on the target surface to form amide or ester bonds, or is hydrolysed11–15. We report here that the binding of the human C4A isotype involves a direct reaction between amino-nucleophiles and the thioester. A two-step mechanism is used by the C4B isotype. The histidine at position 1,106 (aspartic acid in C4A) first attacks the thioester to form an acyl-imidazole intermediate. The released thiol then acts as a base to catalyse the transfer of the acyl group to amino- and hydroxyl-nucleophiles, including water.

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Author notes

  1. Xiang-Dong Ren

    Present address: Department of Vascular Biology, VB-4, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, California, 92037, USA

  2. S. K. Alex Law: To whom correspondence should be addressed.

Authors and Affiliations

  1. The MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

    Alister W. Dodds, Xiang-Dong Ren, Antony C. Willis & S. K. Alex Law

Authors
  1. Alister W. Dodds
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  2. Xiang-Dong Ren
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  3. Antony C. Willis
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  4. S. K. Alex Law
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Dodds, A., Ren, XD., Willis, A. et al. The reaction mechanism of the internal thioester in the human complement component C4. Nature 379, 177–179 (1996). https://doi.org/10.1038/379177a0

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