The Chondroitin Sulfate A-binding Site of the VAR2CSA Protein Involves Multiple N-terminal Domains

被引:66
作者
Dahlback, Madeleine [1 ,2 ]
Jorgensen, Lars M. [2 ]
Nielsen, Morten A. [2 ]
Clausen, Thomas M. [2 ]
Ditlev, Sisse B. [2 ]
Resende, Mafalda [2 ]
Pinto, Vera V. [2 ]
Arnot, David E. [2 ,3 ]
Theander, Thor G. [2 ]
Salanti, Ali [2 ]
机构
[1] Univ Copenhagen, Ctr Med Parasitol, Fac Hlth Sci,CSS, Inst Int Hlth Immunol & Microbiol,Dept Int Hlth I, DK-1014 Copenhagen K, Denmark
[2] Rigshosp, Dept Infect Dis, Copenhagen Univ Hosp, CSS, DK-1014 Copenhagen K, Denmark
[3] Univ Edinburgh, Inst Immunol & Infect Res, Ashworth Lab, Edinburgh EH9 3JT, Midlothian, Scotland
基金
新加坡国家研究基金会;
关键词
FALCIPARUM-INFECTED ERYTHROCYTES; PREGNANCY-ASSOCIATED MALARIA; VARIANT SURFACE-ANTIGENS; PLASMODIUM-FALCIPARUM; PARASITE ADHESION; ANTIBODIES; ADHERENCE; GENE; IDENTIFICATION; PROTEOGLYCANS;
D O I
10.1074/jbc.M110.191510
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. Avaccine 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-CIDRPAM 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.
引用
收藏
页码:15908 / 15917
页数:10
相关论文
共 37 条
[1]   Characterization of proteoglycans of human placenta and identification of unique chondroitin sulfate proteoglycans of the intervillous spaces that mediate the adherence of Plasmodium falciparum-infected erythrocytes to the placenta [J].
Achur, RN ;
Valiyaveettil, M ;
Alkhalil, A ;
Ockenhouse, CF ;
Gowda, DC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (51) :40344-40356
[2]   Structural requirements for the adherence of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate proteoglycans of human placenta [J].
Alkhalil, A ;
Achur, RN ;
Valiyaveettil, M ;
Ockenhouse, CF ;
Gowda, DC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (51) :40357-40364
[3]   Characterization of anti-var2CSA-PfEMP1 cytoadhesion inhibitory mouse monoclonal antibodies [J].
Avril, Marion ;
Gamain, Benoit ;
Lepolard, Catherine ;
Viaud, Nicolas ;
Scherf, Artur ;
Gysin, Juerg .
MICROBES AND INFECTION, 2006, 8 (14-15) :2863-2871
[4]   Structural polymorphism and diversifying selection on the pregnancy malaria vaccine candidate VAR2CSA [J].
Bockhorst, Joseph ;
Lu, Fangli ;
Janes, Joel H. ;
Keebler, Jon ;
Gamain, Benoit ;
Awadalla, Philip ;
Su, Xin-zhuan ;
Samudrala, Ram ;
Jojica, Nebojsa ;
Smith, Joseph D. .
MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 2007, 155 (02) :103-112
[5]   The sick placenta -: The role of malaria [J].
Brabin, BJ ;
Romagosa, C ;
Abdelgalil, S ;
Menéndez, C ;
Verhoeff, FH ;
McGready, R ;
Fletcher, KA ;
Owens, S ;
d'Alessandro, U ;
Nosten, F ;
Fischer, PR ;
Ordi, J .
PLACENTA, 2004, 25 (05) :359-378
[6]   Carbohydrate binding molecules in malaria pathology [J].
Brown, Alan ;
Higgins, Matthew K. .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 2010, 20 (05) :560-566
[7]   The semiconserved head structure of Plasmodium falciparum erythrocyte membrane protein 1 mediates binding to multiple independent host receptors [J].
Chen, QJ ;
Heddini, A ;
Barragan, A ;
Fernandez, V ;
Pearce, SFA ;
Wahlgren, M .
JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 192 (01) :1-9
[8]   Can any lessons be learned from the ambiguous glycan binding of PfEMP1 domains? [J].
Dahlback, Madeleine ;
Nielsen, Morten A. ;
Salanti, Ali .
TRENDS IN PARASITOLOGY, 2010, 26 (05) :230-235
[9]   Var2CSA DBL6-epsilon domain expressed in HEK293 induces limited cross-reactive and blocking antibodies to CSA binding parasites [J].
Fernandez, Pablo ;
KViebig, Nicola ;
Dechavanne, Sebastien ;
Lepolard, Catherine ;
Gysin, Juerg ;
Scherf, Artur ;
Gamain, Benoit .
MALARIA JOURNAL, 2008, 7 (1)
[10]   Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta [J].
Fried, M ;
Duffy, PE .
SCIENCE, 1996, 272 (5267) :1502-1504