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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • 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 Agerbaek
  • Kresten Lindorff-Larsen
  • Morten A. Nielsen
  • Thor G. Theander
  • Joshua S. Sharp
  • Thomas Mandel Clausen
  • Pontus Gourdon
  • Ali Salanti
Enheter & grupper
Externa organisationer
  • University of Copenhagen
  • University of Mississippi
  • University of California, San Diego
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biokemi och molekylärbiologi
Originalspråkengelska
Artikelnummer2956
TidskriftNature Communications
Volym12
StatusPublished - 2021 dec
PublikationskategoriForskning
Peer review utfördJa