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TitleStructural basis for placental malaria mediated by Plasmodium falciparum VAR2CSA.
Journal, issue, pagesNat Microbiol, Vol. 6, Issue 3, Page 380-391, Year 2021
Publish dateJan 15, 2021
AuthorsRui Ma / Tengfei Lian / Rick Huang / Jonathan P Renn / Jennifer D Petersen / Joshua Zimmerberg / Patrick E Duffy / Niraj H Tolia /
PubMed AbstractPlasmodium falciparum VAR2CSA binds to chondroitin sulfate A (CSA) on the surface of the syncytiotrophoblast during placental malaria. This interaction facilitates placental sequestration of malaria ...Plasmodium falciparum VAR2CSA binds to chondroitin sulfate A (CSA) on the surface of the syncytiotrophoblast during placental malaria. This interaction facilitates placental sequestration of malaria parasites resulting in severe health outcomes for both the mother and her offspring. Furthermore, CSA is presented by diverse cancer cells and specific targeting of cells by VAR2CSA may become a viable approach for cancer treatment. In the present study, we determined the cryo-electron microscopy structures of the full-length ectodomain of VAR2CSA from P. falciparum strain NF54 in complex with CSA, and VAR2CSA from a second P. falciparum strain FCR3. The architecture of VAR2CSA is composed of a stable core flanked by a flexible arm. CSA traverses the core domain by binding within two channels and CSA binding does not induce major conformational changes in VAR2CSA. The CSA-binding elements are conserved across VAR2CSA variants and are flanked by polymorphic segments, suggesting immune selection outside the CSA-binding sites. This work provides paths for developing interventions against placental malaria and cancer.
External linksNat Microbiol / PubMed:33452495 / PubMed Central
MethodsEM (single particle)
Resolution3.36 - 4.88 Å
Structure data

22323

7jgd

EMDB-22323, PDB-7jgd:
Cryo-EM structure of P. falciparum VAR2CSA FCR3 core at 3.4 A
Method: EM (single particle) / Resolution: 3.38 Å

22324

7jge

EMDB-22324, PDB-7jge:
Cryo-EM structure of P. falciparum VAR2CSA FCR3 core at 4 A
Method: EM (single particle) / Resolution: 4.0 Å

22325

7jgf

EMDB-22325, PDB-7jgf:
Cryo-EM structure of P. falciparum VAR2CSA FCR3 domains DBL5 and DBL6 at 4.69 A
Method: EM (single particle) / Resolution: 4.69 Å

22326

7jgg

EMDB-22326, PDB-7jgg:
Cryo-EM structure of P. falciparum VAR2CSA NF45 DBL5 and DBL6 domains at 4.88 A
Method: EM (single particle) / Resolution: 4.88 Å

22327

7jgh

EMDB-22327, PDB-7jgh:
Cryo-EM structure of P. falciparum VAR2CSA NF54 core in complex with CSA at 3.36 A
Method: EM (single particle) / Resolution: 3.36 Å

Chemicals

ChemComp-ASG:
2-acetamido-2-deoxy-4-O-sulfo-beta-D-galactopyranose

Source
  • plasmodium falciparum (malaria parasite P. falciparum)
  • plasmodium falciparum (isolate nf54) (eukaryote)
KeywordsSUGAR BINDING PROTEIN / Placental malaria / VAR2CSA / Duffy binding domain / CSA / PfEMP1

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