Structural Insight into Epitopes in the Pregnancy-Associated Malaria Protein VAR2CSA

P Andersen, MA Nielsen, M Resende, Thomas Salhøj Rask, M Dahlbäck, T Theander, Ole Lund, A Salanti

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Pregnancy-associated malaria is caused by Plasmodium falciparum malaria parasites binding specifically to chondroitin sulfate A in the placenta. This sequestration of parasites is a major cause of low birth weight in infants and anemia in the mothers. VAR2CSA, a polymorphic multi-domain protein of the PfEMP1 family, is the main parasite ligand for CSA binding, and identification of protective antibody epitopes is essential for VAR2CSA vaccine development. Attempts to determine the crystallographic structures of VAR2CSA or its domains have not been successful yet. In this study, we propose 3D models for each of the VAR2CSA DBL domains and we show that regions in the fold of VAR2CSA inter-domain 2 and a PfEMP1 CIDR domain seem to be homologous to the EBA-175 and Pkα-DBL fold. This suggests that ID2 could be a functional domain. We also identify regions of VAR2CSA present on the surface of native VAR2CSA by comparing reactivity of plasma containing anti-VAR2CSA antibodies in peptide array experiments before and after incubation with native VAR2CSA. By this method we identify conserved VAR2CSA regions targeted by antibodies that react with the native molecule expressed on infected erythrocytes. By mapping the data onto the DBL models we present evidence suggesting that the S1+S2 DBL sub-domains are generally surface-exposed in most domains, whereas the S3 sub-domains are less exposed in native VAR2CSA. These results comprise an important step towards understanding the structure of VAR2CSA on the surface of CSA-binding infected erythrocytes.
    Original languageEnglish
    JournalP L o S Pathogens
    Volume4
    Issue number2
    Pages (from-to)42
    ISSN1553-7366
    DOIs
    Publication statusPublished - 2008

    Cite this

    Andersen, P., Nielsen, MA., Resende, M., Rask, T. S., Dahlbäck, M., Theander, T., ... Salanti, A. (2008). Structural Insight into Epitopes in the Pregnancy-Associated Malaria Protein VAR2CSA. P L o S Pathogens, 4(2), 42. https://doi.org/10.1371/journal.ppat.0040042
    Andersen, P ; Nielsen, MA ; Resende, M ; Rask, Thomas Salhøj ; Dahlbäck, M ; Theander, T ; Lund, Ole ; Salanti, A. / Structural Insight into Epitopes in the Pregnancy-Associated Malaria Protein VAR2CSA. In: P L o S Pathogens. 2008 ; Vol. 4, No. 2. pp. 42.
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    title = "Structural Insight into Epitopes in the Pregnancy-Associated Malaria Protein VAR2CSA",
    abstract = "Pregnancy-associated malaria is caused by Plasmodium falciparum malaria parasites binding specifically to chondroitin sulfate A in the placenta. This sequestration of parasites is a major cause of low birth weight in infants and anemia in the mothers. VAR2CSA, a polymorphic multi-domain protein of the PfEMP1 family, is the main parasite ligand for CSA binding, and identification of protective antibody epitopes is essential for VAR2CSA vaccine development. Attempts to determine the crystallographic structures of VAR2CSA or its domains have not been successful yet. In this study, we propose 3D models for each of the VAR2CSA DBL domains and we show that regions in the fold of VAR2CSA inter-domain 2 and a PfEMP1 CIDR domain seem to be homologous to the EBA-175 and Pkα-DBL fold. This suggests that ID2 could be a functional domain. We also identify regions of VAR2CSA present on the surface of native VAR2CSA by comparing reactivity of plasma containing anti-VAR2CSA antibodies in peptide array experiments before and after incubation with native VAR2CSA. By this method we identify conserved VAR2CSA regions targeted by antibodies that react with the native molecule expressed on infected erythrocytes. By mapping the data onto the DBL models we present evidence suggesting that the S1+S2 DBL sub-domains are generally surface-exposed in most domains, whereas the S3 sub-domains are less exposed in native VAR2CSA. These results comprise an important step towards understanding the structure of VAR2CSA on the surface of CSA-binding infected erythrocytes.",
    author = "P Andersen and MA Nielsen and M Resende and Rask, {Thomas Salh{\o}j} and M Dahlb{\"a}ck and T Theander and Ole Lund and A Salanti",
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    doi = "10.1371/journal.ppat.0040042",
    language = "English",
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    Andersen, P, Nielsen, MA, Resende, M, Rask, TS, Dahlbäck, M, Theander, T, Lund, O & Salanti, A 2008, 'Structural Insight into Epitopes in the Pregnancy-Associated Malaria Protein VAR2CSA', P L o S Pathogens, vol. 4, no. 2, pp. 42. https://doi.org/10.1371/journal.ppat.0040042

    Structural Insight into Epitopes in the Pregnancy-Associated Malaria Protein VAR2CSA. / Andersen, P; Nielsen, MA; Resende, M; Rask, Thomas Salhøj; Dahlbäck, M; Theander, T; Lund, Ole; Salanti, A.

    In: P L o S Pathogens, Vol. 4, No. 2, 2008, p. 42.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    T1 - Structural Insight into Epitopes in the Pregnancy-Associated Malaria Protein VAR2CSA

    AU - Andersen, P

    AU - Nielsen, MA

    AU - Resende, M

    AU - Rask, Thomas Salhøj

    AU - Dahlbäck, M

    AU - Theander, T

    AU - Lund, Ole

    AU - Salanti, A

    PY - 2008

    Y1 - 2008

    N2 - Pregnancy-associated malaria is caused by Plasmodium falciparum malaria parasites binding specifically to chondroitin sulfate A in the placenta. This sequestration of parasites is a major cause of low birth weight in infants and anemia in the mothers. VAR2CSA, a polymorphic multi-domain protein of the PfEMP1 family, is the main parasite ligand for CSA binding, and identification of protective antibody epitopes is essential for VAR2CSA vaccine development. Attempts to determine the crystallographic structures of VAR2CSA or its domains have not been successful yet. In this study, we propose 3D models for each of the VAR2CSA DBL domains and we show that regions in the fold of VAR2CSA inter-domain 2 and a PfEMP1 CIDR domain seem to be homologous to the EBA-175 and Pkα-DBL fold. This suggests that ID2 could be a functional domain. We also identify regions of VAR2CSA present on the surface of native VAR2CSA by comparing reactivity of plasma containing anti-VAR2CSA antibodies in peptide array experiments before and after incubation with native VAR2CSA. By this method we identify conserved VAR2CSA regions targeted by antibodies that react with the native molecule expressed on infected erythrocytes. By mapping the data onto the DBL models we present evidence suggesting that the S1+S2 DBL sub-domains are generally surface-exposed in most domains, whereas the S3 sub-domains are less exposed in native VAR2CSA. These results comprise an important step towards understanding the structure of VAR2CSA on the surface of CSA-binding infected erythrocytes.

    AB - Pregnancy-associated malaria is caused by Plasmodium falciparum malaria parasites binding specifically to chondroitin sulfate A in the placenta. This sequestration of parasites is a major cause of low birth weight in infants and anemia in the mothers. VAR2CSA, a polymorphic multi-domain protein of the PfEMP1 family, is the main parasite ligand for CSA binding, and identification of protective antibody epitopes is essential for VAR2CSA vaccine development. Attempts to determine the crystallographic structures of VAR2CSA or its domains have not been successful yet. In this study, we propose 3D models for each of the VAR2CSA DBL domains and we show that regions in the fold of VAR2CSA inter-domain 2 and a PfEMP1 CIDR domain seem to be homologous to the EBA-175 and Pkα-DBL fold. This suggests that ID2 could be a functional domain. We also identify regions of VAR2CSA present on the surface of native VAR2CSA by comparing reactivity of plasma containing anti-VAR2CSA antibodies in peptide array experiments before and after incubation with native VAR2CSA. By this method we identify conserved VAR2CSA regions targeted by antibodies that react with the native molecule expressed on infected erythrocytes. By mapping the data onto the DBL models we present evidence suggesting that the S1+S2 DBL sub-domains are generally surface-exposed in most domains, whereas the S3 sub-domains are less exposed in native VAR2CSA. These results comprise an important step towards understanding the structure of VAR2CSA on the surface of CSA-binding infected erythrocytes.

    U2 - 10.1371/journal.ppat.0040042

    DO - 10.1371/journal.ppat.0040042

    M3 - Journal article

    VL - 4

    SP - 42

    JO - P L o S Pathogens

    JF - P L o S Pathogens

    SN - 1553-7366

    IS - 2

    ER -