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Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain

Abstract

Molecular processes that govern pathogenic features of erythrocyte invasion and cytoadherence in malaria are reliant on Plasmodium-specific Duffy-binding-like domains (DBLs)1. These cysteine-rich modules recognize diverse host cell-surface receptors during pathogenesis. DBLs of parasite erythrocyte-binding proteins mediate invasion, and those from the antigenically variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) have been implicated in cytoadherence. The simian and human malarial parasites, P. knowlesi and P. vivax, invade human erythrocytes exclusively through the host DARC receptor (Duffy antigen receptor for chemokines)2,3. Here we present the crystal structure of the P. knowlesi DBL domain (Pkα-DBL), which binds to DARC during invasion of human erythrocytes. Pkα-DBL retains the overall fold observed in DBLs from P. falciparum erythrocyte-binding antigen (EBA)-175 (ref. 4). Mapping the residues that have previously been implicated in binding5,6,7 highlights a fairly flat but exposed site for DARC recognition in subdomain 2 of Pkα-DBL; this is in sharp contrast to receptor recognition by EBA-175 (ref. 4). In Pkα-DBL, the residues that contact DARC and the clusters of residues under immune pressure map to opposite surfaces of the DBL, and suggest a possible mechanism for immune evasion by P. vivax. Our comparative structural analysis of Pkα-DBL and P. falciparum EBA-175 provides a framework for the understanding of malaria parasite DBLs, and may affect the development of new prophylactic and therapeutic strategies.

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Figure 1: Structure of Pkα-DBL.
Figure 2: Disulphide bond distribution.
Figure 3: DARC recognition site.
Figure 4: Model of Pv-DBL–erythrocyte interaction.

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Acknowledgements

We thank D. Stuart and M. Walsh for facilitating data collection. We also thank past and present members of ICGEB, A. Rushdi Shakri and S. Krishnaswamy for help. C.E.C. is a Howard Hughes International Research Scholar. The Sharma laboratory is supported by a grant from the European Commission FP6. C.E.C. and A.S. are International Wellcome Trust Senior Research Fellows.

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Correspondence to Amit Sharma.

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Atomic coordinates for Pkα-DBL have been deposited in the Protein Data Bank under accession number 2c6j. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1 and 2. Supplementary Figure 1 details the disulphide structure of DBLs. Supplementary figure 2 details the specific binding of recombinant PkαDBL to human DARC (PDF 122 kb)

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Singh, S., Hora, R., Belrhali, H. et al. Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain. Nature 439, 741–744 (2006). https://doi.org/10.1038/nature04443

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