Journal of Biological Chemistry
Volume 277, Issue 31, 2 August 2002, Pages 27651-27658
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ENZYME CATALYSIS AND REGULATION
A Mosquito Salivary Protein Inhibits Activation of the Plasma Contact System by Binding to Factor XII and High Molecular Weight Kininogen*

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The salivary glands of female mosquitoes contain a variety of bioactive substances that assist their blood-feeding behavior. Here, we report a salivary protein of the malarial vector mosquito, Anopheles stephensi, that inhibits activation of the plasma contact system. This factor, named hamadarin, is a 16-kDa protein and a major component of the saliva of this mosquito. Assays using human plasma showed that hamadarin dose-dependently inhibits activation of the plasma contact system and subsequent release of bradykinin, a primary mediator of inflammatory reactions. Reconstitution experiments showed that hamadarin inhibits activation of the plasma contact system by inhibition of the reciprocal activation of factor XII and kallikrein. Direct binding assays demonstrated that this inhibitory effect is due to hamadarin binding to both factor XII and high molecular weight kininogen and interference in their association with the activating surface. The assays also showed that hamadarin binding to these proteins depends on Zn2+ ions, suggesting that hamadarin binds to these contact factors by recognizing their conformational change induced by Zn2+ binding. We propose that hamadarin may attenuate the host's acute inflammatory responses to the mosquito's bites by inhibition of bradykinin release and thus enable mosquitoes to take a blood meal efficiently and safely.

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Published, JBC Papers in Press, May 13, 2002, DOI 10.1074/jbc.M203505200

AY091601

*

This work was supported by grants-in-aid for Scientific Research on Priority Areas (08281103 to Y. C.), for Scientific Research (B) (12470060 to M. Y.), and for Exploratory Research (10877043, 11877043, and 12877042 to Y. C.) from the Ministry of Education, Science, Culture and Sports of Japan and by grants from the Research for the Future Program from the Japan Society for the Promotion of Science (JSPS) (to Y. C.) and from the JSPS Research Fellowships for Young Scientists (to H. I.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EBI Data Bank with accession number(s) .