Structural basis for placental malaria mediated by Plasmodium falciparum VAR2CSA.
Open accessAbstract
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.
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Allelic variation in VAR2CSA proteins did not seem to affect the structure.
“Allelic variation in VAR2CSA proteins did not seem to affect this structure [8]”
From A conformational epitope in placental malaria vaccine antigen VAR2CSA: What does it teach us? (2023) · cites this paper as [8]
The full-length VAR2CSA ectodomain is composed of a stable core (NTS-DBL4) with CSA-binding channel(s) and a flexible arm (DBL5-6).
“Recent studies have described the molecular structure of the full-length VAR2CSA ectodomain, revealing that VAR2CSA is composed of a stable core (NTS-DBL4) with CSA-binding channel(s) and a flexible arm (DBL5-6) [8,9].”
From A conformational epitope in placental malaria vaccine antigen VAR2CSA: What does it teach us? (2023) · cites this paper as [8]
In areas of high P. falciparum transmission, pregnant women develop partial immunity to placental infection through repeated malaria exposure over successive pregnancies.
“In areas of high P. falciparum transmission, pregnant women develop partial immunity to placental infection through repeated malaria exposure over successive pregnancies [7–10].”
From Global estimates of pregnancies at risk of Plasmodium falciparum and Plasmodium vivax infection in 2020 and changes in risk patterns since 2000 (2022) · cites this paper as [10]
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References 79 · Cited by 72
- Authors
- Ma, R., Lian, T., Huang, R., Renn, J. P., Petersen, J. D., Zimmerberg, J., Duffy, P. E., & Tolia, N. H.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Tolia, Niraj H.
- ORCID
- Venue
- Nature Microbiology
- Published
- 2021-01-15
- Volume
- 6
- Issue
- 3
- Pages
- 380-391
- ISSN
- 2058-5276 (ISSN-L)
- PMC
- PMC7914210
- OpenAlex
- W3125344209
- Cited by
- 72
- References
- 79
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 11 · 2023: 16 · 2022: 16 · 2021: 12
- FWCI
- 11.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (1ZIAAI001237, 1ZIAAI001236, 1ZIAAI001253)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Health Sciences › Medicine › Hematology › Blood groups and transfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- placental malaria, Plasmodium falciparum, VAR2CSA, chondroitin sulfate A, syncytiotrophoblast, parasite sequestration, protein-carbohydrate binding, cryo-EM structure, conformational flexibility, immune selection, tumor targeting
- MeSH terms
- Protein Domains, Epitopes, Antigens, Protozoan, Binding Sites, Chondroitin Sulfates, Female, Humans, Placenta, Plasmodium falciparum, Pregnancy, Protein Binding, Genetic Variation, Pregnancy Complications, Parasitic, Malaria, Falciparum, Malaria Vaccines, Cryoelectron Microscopy
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