Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

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 Agerbaek, Kresten Lindorff-Larsen, Morten A. Nielsen, Thor G. Theander, Joshua S. Sharp, Thomas Mandel Clausen, Pontus Gourdon () and Ali Salanti ()
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Kaituo Wang: University of Copenhagen
Robert Dagil: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Thomas Lavstsen: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Sandeep K. Misra: University of Mississippi
Charlotte B. Spliid: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Yong Wang: University of Copenhagen
Tobias Gustavsson: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Daniel R. Sandoval: University of California, San Diego
Elena Ethel Vidal-Calvo: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Swati Choudhary: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Mette Ø Agerbaek: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Kresten Lindorff-Larsen: University of Copenhagen
Morten A. Nielsen: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Thor G. Theander: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital
Joshua S. Sharp: University of Mississippi
Thomas Mandel Clausen: University of California, San Diego
Pontus Gourdon: University of Copenhagen
Ali Salanti: University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.

Date: 2021
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DOI: 10.1038/s41467-021-23254-1

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