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Infection and Immunity, August 2005, p. 4478-4487, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.4478-4487.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

N-Linked Glycosylation at Asn3 and the Positively Charged Residues within the Amino-Terminal Domain of the C1 Inhibitor Are Required for Interaction of the C1 Inhibitor with Salmonella enterica Serovar Typhimurium Lipopolysaccharide and Lipid A

Dongxu Liu, Cort C. Cramer, Jennifer Scafidi, and Alvin E. Davis III*

The CBR Institute for Biomedical Research, Harvard Medical School, 800 Huntington Avenue, Boston, Massachusetts 02115

Received 6 January 2005/ Returned for modification 25 January 2005/ Accepted 2 March 2005

The C1 inhibitor (C1INH), a plasma complement regulatory protein, prevents endotoxin shock, at least partially via the direct interaction of its amino-terminal heavily glycosylated nonserpin region with gram-negative bacterial lipopolysaccharide (LPS). To further characterize the potential LPS-binding site(s) within the amino-terminal domain, mutations were introduced into C1INH at the three N-linked glycosylation sites and at the four positively charged amino acid residues. A mutant in which Asn3 was replaced with Ala was markedly less effective in its binding to LPS, while substitution of Asn47 or Asn59 had little effect on binding. The mutation of C1INH at all four positively charged amino acid residues (Arg18, Lys22, Lys30, and Lys55) resulted in near-complete failure to interact with LPS. The C1INH mutants that did not bind to LPS also did not suppress LPS binding or LPS-induced up-regulation of tumor necrosis factor alpha mRNA expression in RAW 264.7 macrophages. In addition, the binding of C1INH mutants to diphosphoryl lipid A was decreased in comparison with that of recombinant wild-type C1INH. Therefore, the interaction of C1INH with gram-negative bacterial LPS is dependent both on the N-linked carbohydrate at Asn3 and on the positively charged residues within the amino-terminal domain.

* Corresponding author. Mailing address: The CBR Institute for Biomedical Research, Harvard Medical School, 800 Huntington Avenue, Boston, MA 02115. Phone: (617) 278-3379. Fax: (617) 278-3490. E-mail: aldavis{at}cbr.med.harvard.edu.

Editor: A. D. O'Brien

Infection and Immunity, August 2005, p. 4478-4487, Vol. 73, No. 8
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.8.4478-4487.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Liu, D., Lu, F., Qin, G., Fernandes, S. M., Li, J., Davis, A. E. III (2007). C1 Inhibitor-Mediated Protection from Sepsis. J. Immunol. 179: 3966-3972 [Abstract] [Full Text]  


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