7Z12

VAR2 complex with PAM1.4

Summary for 7Z12

• Entry DOI: 10.2210/pdb7z12/pdb
• EMDB information: 14438
• Descriptor: PAM1.4, Heavy Chain, PAM1.4, light Chain, VAR2CSA (3 entities in total)
• Functional Keywords: var2csa, malaria, cell adhesion
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 312339.23

Authors

Raghavan, S.S.R.,Wang, K.T. (deposition date: 2022-02-24, release date: 2022-11-02, Last modification date: 2022-11-30)

Primary citation

Raghavan, S.S.R.,Dagil, R.,Lopez-Perez, M.,Conrad, J.,Bassi, M.R.,Quintana, M.D.P.,Choudhary, S.,Gustavsson, T.,Wang, Y.,Gourdon, P.,Ofori, M.F.,Christensen, S.B.,Minja, D.T.R.,Schmiegelow, C.,Nielsen, M.A.,Barfod, L.,Hviid, L.,Salanti, A.,Lavstsen, T.,Wang, K.
Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA.
Plos Pathog., 18:e1010924-e1010924, 2022

PubMed Abstract: Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria.

PubMed: 36383559
DOI: 10.1371/journal.ppat.1010924

Experimental method

ELECTRON MICROSCOPY (3 Å)