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J. Biol. Chem., Vol. 282, Issue 32, 23447-23456, August 10, 2007

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Structural and Functional Characterization of a Secreted Hookworm Macrophage Migration Inhibitory Factor (MIF) That Interacts with the Human MIF Receptor CD74^*

Yoonsang Cho¹, Brian F. Jones¹, Jon J. Vermeire, Lin Leng^¶, Lisa DiFedele, Lisa M. Harrison, Huabao Xiong^||, Yuen-Kwan Amy Kwong^||, Yibang Chen^||, Richard Bucala^¶, Elias Lolis², and Michael Cappello³

From the Department of Pharmacology, the Program in International Child Health and Department of Pediatrics, and the ^¶Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520 and the ^||Department of Pharmacology, Immunobiology Center, Mt. Sinai School of Medicine, New York, New York 10029

Hookworms, parasitic nematodes that infect nearly one billion people worldwide, are a major cause of anemia and malnutrition. We hypothesize that hookworms actively manipulate the host immune response through the production of specific molecules designed to facilitate infection by larval stages and adult worm survival within the intestine. A full-length cDNA encoding a secreted orthologue of the human cytokine, Macrophage Migration Inhibitory Factor (MIF) has been cloned from the hookworm Ancylostoma ceylanicum. Elucidation of the three-dimensional crystal structure of recombinant AceMIF (rAceMIF) revealed an overall structural homology with significant differences in the tautomerase sites of the human and hookworm proteins. The relative bioactivities of human and hookworm MIF proteins were compared using in vitro assays of tautomerase activity, macrophage migration, and binding to MIF receptor CD74. The activity of rAceMIF was not inhibited by the ligand ISO-1, which was previously determined to be an inhibitor of the catalytic site of human MIF. These data define unique immunological, structural, and functional characteristics of AceMIF, thereby establishing the potential for selectively inhibiting the hookworm cytokine as a means of reducing parasite survival and disease pathogenesis.

Received for publication, April 6, 2007 , and in revised form, May 25, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) EF410151.

The atomic coordinates and structure factors (code 2OS5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grants AI065029 (to E. L.), AI42310 (to R. B.), AI51306 (to R. B.), AI007404 (to J. J. V.), and AI058980 (to M. C.). 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.

¹ Both authors contributed equally.

² To whom correspondence may be addressed: Dept. of Pharmacology, Yale University School of Medicine, New Haven, CT 06520. E-mail: elias.lolis{at}yale.edu. ³ To whom correspondence may be addressed: Dept. of Pediatrics, Yale University School of Medicine, New Haven, CT 06520. E-mail: michael.cappello{at}yale.edu.

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