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Cryo-electron microscopy of IgM-VAR2CSA complex reveals IgM inhibits binding of Plasmodium falciparum to Chondroitin Sulfate A

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  • Reetesh Raj Akhouri

    (Okinawa Institute of Science and Technology Graduate University
    Indian Institute of Technology Madras)

  • Suchi Goel

    (Indian Institute of Science Education and Research Tirupati)

  • Ulf Skoglund

    (Okinawa Institute of Science and Technology Graduate University)

Abstract

Placental malaria is caused by Plasmodium falciparum-infected erythrocytes (IEs) adhering to chondroitin sulfate proteoglycans in placenta via VAR2CSA-type PfEMP1. Human pentameric immunoglobulin M (IgM) binds to several types of PfEMP1, including VAR2CSA via its Fc domain. Here, a 3.6 Å cryo-electron microscopy map of the IgM-VAR2CSA complex reveals that two molecules of VAR2CSA bind to the Cµ4 of IgM through their DBL3X and DBL5ε domains. The clockwise and anti-clockwise rotation of the two VAR2CSA molecules on opposite faces of IgM juxtaposes C-termini of both VAR2CSA near the J chain, where IgM creates a wall between both VAR2CSA molecules and hinders its interaction with its receptor. To support this, we show when VAR2CSA is bound to IgM, its staining on IEs as well as binding of IEs to chondroitin sulfate A in vitro is severely compromised.

Suggested Citation

  • Reetesh Raj Akhouri & Suchi Goel & Ulf Skoglund, 2023. "Cryo-electron microscopy of IgM-VAR2CSA complex reveals IgM inhibits binding of Plasmodium falciparum to Chondroitin Sulfate A," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41838-x
    DOI: 10.1038/s41467-023-41838-x
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    References listed on IDEAS

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    1. 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.
    2. Kaituo Wang & Robert Dagil & Thomas Lavstsen & Sandeep K. Misra & Charlotte B. Spliid & Yong Wang & Tobias Gustavsson & Daniel R. Sandoval & Elena Ethel Vidal-Calvo & Swati Choudhary & Mette Ø Agerbae, 2021. "Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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    1. 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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