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J. Biol. Chem., Vol. 282, Issue 6, 3962-3967, February 9, 2007

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A Structural Perspective on the Interaction between Lipopolysaccharide and Factor C, a Receptor Involved in Recognition of Gram-negative Bacteria^*

From the Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan

The recognition of broadly conserved microorganism components known as pathogen-associated molecular patterns is an essential step in initiating the innate immune response. In the horseshoe crab, stimulation of hemocytes with lipopolysaccharide (LPS) causes the activation of its innate immune response, and Factor C, a serine protease zymogen, plays an important role in this event. Here, we report that Factor C associates with LPS on the hemocyte surface and directly recognizes Gram-negative bacteria. Structure-function analyses reveal that the LPS binding site is present in the N-terminal cysteine-rich (Cys-rich) region of the molecule and that it contains a tripeptide sequence consisting of an aromatic residue flanked by two basic residues that is conserved in other mammalian LPS-recognizing proteins. Moreover, we have demonstrated that the Cys-rich region specifically binds to LPS on Gram-negative bacteria and that mutations in the tripeptide motif abrogate its association with both LPS and Gram-negative bacteria, underscoring the importance of the tripeptide in LPS interaction. Although the innate immune response to LPS in the horseshoe crab is distinct from that of mammals, it appears to rely on structural features that are conserved among LPS-recognizing proteins from diverse species.

Received for publication, September 28, 2006 , and in revised form, November 15, 2006.

^* This work was supported by the grants-in-aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18770137) and Kato Memorial Bioscience Foundation (to T. K.), the Naito Foundation, Japan Foundation for Applied Enzymology, and grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to S. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: Dept. of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku Fukuoka 812-8581, Japan. Tel.: 81-92-642-2632; Fax: 81-92-642-2632; E-mail: skawascb{at}mbox.nc.kyushu-u.ac.jp.

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