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Dimerization of Plasmodium vivax DBP is induced upon receptor binding and drives recognition of DARC

Nature Structural & Molecular Biology volume 18, pages 908–914 (2011)Cite this article

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Abstract

Plasmodium vivax and Plasmodium knowlesi invasion depends on the parasite Duffy-binding protein DBL domain (RII-PvDBP or RII-PkDBP) engaging the Duffy antigen receptor for chemokines (DARC) on red blood cells. Inhibition of this key interaction provides an excellent opportunity for parasite control. There are competing models for whether Plasmodium ligands engage receptors as monomers or dimers, a question whose resolution has profound implications for parasite biology and control. We report crystallographic, solution and functional studies of RII-PvDBP showing that dimerization is required for and driven by receptor engagement. This work provides a unifying framework for prior studies and accounts for the action of naturally acquired blocking antibodies and the mechanism of immune evasion. We show that dimerization is conserved in DBL-domain receptor engagement and propose that receptor-mediated ligand dimerization drives receptor affinity and specificity. Because dimerization is prevalent in signaling, our studies raise the possibility that induced dimerization may activate pathways for invasion.

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Figure 1: RII-PvDBP is composed of three subdomains, and a sulfotyrosine pocket within a DARC-binding groove is formed by the RII-PvDBP dimer.
Figure 2: DARC binding drives dimerization of RII-PvDBP.
Figure 3: The sulfotyrosine pocket, DARC-binding groove and dimer interface are under selective pressure and are targeted by blocking antibodies.
Figure 4: RII-PvDBP's dimer interface and receptor binding site are conserved in VAR2CSA DBL6ɛ.
Figure 5: PvDBP binds DARC via a model of receptor-mediated ligand-dimerization.

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Acknowledgements

We thank S. Beverley, D. Fremont, L. Joshua-Tor, D. Goldberg, D. Sibley, J. Vogel and E. Chen for constructive comments on the manuscript, J. Adams (University of South Florida) for providing RII-PvDBP DNA and D. Goldberg (Washington University) for additional reagents. We thank T. Lohman and R. Galletto for assistance with the AUC experiments, D. Fremont and T. Brett for assistance with the ITC experiments, J. Nix and the Molecular Biology Consortium Collaborative Access Team at the Advanced Light Source for assistance in crystallographic data collection, and G. Hura, K. Dyer and the Structurally Integrated Biology for Life Sciences Team at the Advanced Light Source for assistance in SAXS data collection funded by US Department of Energy Integrated Diffraction Analysis Technologies grant contract number DE-AC02-05CH11231. The project described was supported by grant number 080792 from the US National Institute of Allergy and Infectious Disease to N.H.T., and by US National Institutes of Health Training Grant no. AI007172 and a W.M. Keck Postdoctoral Fellowship to J.D.B.

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  1. Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USA

    Joseph D Batchelor, Jacob A Zahm & Niraj H Tolia

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  1. Joseph D Batchelor
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  2. Jacob A Zahm
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Contributions

J.D.B. performed functional assays, SAXS data analysis, AUC studies, ITC studies and structure analyses. J.A.Z. cloned, purified and crystallized RII-PvDBP. N.H.T. designed the study, analyzed SAXS data, collected, processed and refined X-ray data, and analyzed the structure. All authors were involved in writing the paper, discussed the results and commented on the manuscript.

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Correspondence to Niraj H Tolia.

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Batchelor, J., Zahm, J. & Tolia, N. Dimerization of Plasmodium vivax DBP is induced upon receptor binding and drives recognition of DARC. Nat Struct Mol Biol 18, 908–914 (2011). https://doi.org/10.1038/nsmb.2088

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