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

Wang, Kaituo ; Dagil, Robert ; Lavstsen, Thomas ; Misra, Sandeep K. ; Spliid, Charlotte B. ; Wang, Yong ; Gustavsson, Tobias ; Sandoval, Daniel R. ; Vidal-Calvo, Elena Ethel and Choudhary, Swati , et al. (2021) In Nature Communications 12.
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... (More)

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.

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type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
article number
2956
publisher
Nature Publishing Group
external identifiers
  • pmid:34011972
  • scopus:85106050149
ISSN
2041-1723
DOI
10.1038/s41467-021-23254-1
language
English
LU publication?
yes
id
ab0a7823-57ff-4718-a5dd-aed3ab7bc556
date added to LUP
2021-06-02 16:05:21
date last changed
2024-09-08 19:03:35
@article{ab0a7823-57ff-4718-a5dd-aed3ab7bc556,
  abstract     = {{<p>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.</p>}},
  author       = {{Wang, Kaituo and Dagil, Robert and Lavstsen, Thomas and Misra, Sandeep K. and Spliid, Charlotte B. and Wang, Yong and Gustavsson, Tobias and Sandoval, Daniel R. and Vidal-Calvo, Elena Ethel and Choudhary, Swati and Agerbaek, Mette and Lindorff-Larsen, Kresten and Nielsen, Morten A. and Theander, Thor G. and Sharp, Joshua S. and Clausen, Thomas Mandel and Gourdon, Pontus and Salanti, Ali}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-23254-1}},
  doi          = {{10.1038/s41467-021-23254-1}},
  volume       = {{12}},
  year         = {{2021}},
}