Dobson, S. E., Augustijn, K. D., Brannigan, J. A., Schnick, C., Janse, C. J., Dodson, E. J., Waters, A.P. and Wilkinson, A. J. (2009) The crystal structures of macrophage migration inhibitory factor fromPlasmodium falciparumandPlasmodium berghei. Protein Science, 18(12), pp. 2578-2591. (doi: 10.1002/pro.263)
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Publisher's URL: http://dx.doi.org/10.1002/pro.263
Abstract
Malaria, caused by Plasmodium falciparum and related parasites, is responsible for millions of deaths each year, mainly from complications arising from the blood stages of its life cycle. Macrophage migration inhibitory factor (MIF), a protein expressed by the parasite during these stages, has been characterized in mammals as a cytokine involved in a broad spectrum of immune responses. It also possesses two catalytic activites; a tautomerase and an oxidoreductase, though the physiological significance of neither reaction is known. Here, we have determined the crystal structure of MIF from two malaria parasites, Plasmodium falciparumand Plasmodium bergheiat 2.2 Å and 1.8 Å, respectively. The structures have an / fold and each reveals a trimer, in agreement with the results of analytical ultracentrifugation. We observed open and closed active sites, these being distinguished by movements of proline-1, the catalytic base in the tautomerase reaction. These states correlate with the covalent modification of cysteine 2 to form a mercaptoethanol adduct, an observation confirmed by mass spectrometry. The Plasmodium MIFs have a different pattern of conserved cysteine residues to the mammalian MIFs and the side chain of Cys58, which is implicated in the oxidoreductase activity, is buried. This observation and the evident redox reactivity of Cys2 suggest quite different oxidoreductase characteristics. Finally we show in pull-down assays that Plasmodium MIF binds to the cell surface receptor CD74, a known mammalian MIF receptor implying that parasite MIF has the ability to interfere with, or modulate, host MIF activity through a competitive binding mechanism. © 2009 The Protein Society
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Waters, Professor Andy |
Authors: | Dobson, S. E., Augustijn, K. D., Brannigan, J. A., Schnick, C., Janse, C. J., Dodson, E. J., Waters, A.P., and Wilkinson, A. J. |
College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Journal Name: | Protein Science |
ISSN: | 0961-8368 |
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