The chondroitin sulfate A-binding site of the VAR2CSA protein involves multiple N-terminal domains

TY - JOUR

T1 - The chondroitin sulfate A-binding site of the VAR2CSA protein involves multiple N-terminal domains

AU - Dahlbäck, Madeleine

AU - Jørgensen, Lars M

AU - Nielsen, Morten A

AU - Clausen, Thomas M

AU - Ditlev, Sisse B

AU - Resende, Mafalda

AU - Pinto, Vera V

AU - Arnot, David E

AU - Theander, Thor G

AU - Salanti, Ali

PY - 2011/5/6

Y1 - 2011/5/6

N2 - Malaria during pregnancy is a major health problem for African women. The disease is caused by Plasmodium falciparum malaria parasites, which accumulate in the placenta by adhering to chondroitin sulfate A (CSA). The interaction between infected erythrocytes and the placental receptor is mediated by a parasite expressed protein named VAR2CSA. A vaccine protecting pregnant women against placental malaria should induce antibodies inhibiting the interaction between VAR2CSA and CSA. Much effort has been put into defining the part of the 350 kDa VAR2CSA protein that is responsible for binding. It has been shown that full-length recombinant VAR2CSA binds specifically to CSA with high affinity, however to date no sub-fragment of VAR2CSA has been shown to interact with CSA with similar affinity or specificity. In this study, we used a biosensor technology to examine the binding properties of a panel of truncated VAR2CSA proteins. The experiments indicate that the core of the CSA-binding site is situated in three domains, DBL2X-CIDR(PAM) and a flanking domain, located in the N-terminal part of VAR2CSA. Furthermore, recombinant VAR2CSA subfragments containing this region elicit antibodies with high parasite adhesion blocking activity in animal immunization experiments.

AB - Malaria during pregnancy is a major health problem for African women. The disease is caused by Plasmodium falciparum malaria parasites, which accumulate in the placenta by adhering to chondroitin sulfate A (CSA). The interaction between infected erythrocytes and the placental receptor is mediated by a parasite expressed protein named VAR2CSA. A vaccine protecting pregnant women against placental malaria should induce antibodies inhibiting the interaction between VAR2CSA and CSA. Much effort has been put into defining the part of the 350 kDa VAR2CSA protein that is responsible for binding. It has been shown that full-length recombinant VAR2CSA binds specifically to CSA with high affinity, however to date no sub-fragment of VAR2CSA has been shown to interact with CSA with similar affinity or specificity. In this study, we used a biosensor technology to examine the binding properties of a panel of truncated VAR2CSA proteins. The experiments indicate that the core of the CSA-binding site is situated in three domains, DBL2X-CIDR(PAM) and a flanking domain, located in the N-terminal part of VAR2CSA. Furthermore, recombinant VAR2CSA subfragments containing this region elicit antibodies with high parasite adhesion blocking activity in animal immunization experiments.

U2 - 10.1074/jbc.M110.191510

DO - 10.1074/jbc.M110.191510

M3 - Journal article

C2 - 21398524

SN - 0021-9258

VL - 286

SP - 15908

EP - 15917

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 18

ER -