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

Author

Listed:
  • Saurabh Kumar Singh

    (Aruna Asaf Ali Marg)

  • Rachna Hora

    (Aruna Asaf Ali Marg)

  • Hassan Belrhali

    (European Molecular Biology Laboratory (EMBL))

  • Chetan E. Chitnis

    (Aruna Asaf Ali Marg)

  • Amit Sharma

    (Aruna Asaf Ali Marg)

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.

Suggested Citation

  • Saurabh Kumar Singh & Rachna Hora & Hassan Belrhali & Chetan E. Chitnis & Amit Sharma, 2006. "Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain," Nature, Nature, vol. 439(7077), pages 741-744, February.
  • Handle: RePEc:nat:nature:v:439:y:2006:i:7077:d:10.1038_nature04443
    DOI: 10.1038/nature04443
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    Cited by:

    1. Re’em Moskovitz & Tossapol Pholcharee & Sophia M. DonVito & Bora Guloglu & Edward Lowe & Franziska Mohring & Robert W. Moon & Matthew K. Higgins, 2023. "Structural basis for DARC binding in reticulocyte invasion by Plasmodium vivax," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    2. Ifeanyichukwu Okeke & Tanko Ishaya & EO Afolabi, 2020. "Molecular Dynamics Simulation and Analysis of some Ligands on Var2csA Target," Novel Approaches in Drug Designing & Development, Juniper Publishers Inc., vol. 5(4), pages 63-84, October.
    3. Chenggong Ji & Hao Shen & Chen Su & Yaxin Li & Shihua Chen & Thomas H. Sharp & Junyu Xiao, 2023. "Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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