Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition
In: Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 2011, 108 (13), pp.5243-5248. ⟨10.1073/pnas.1018692108⟩ Proceedings of the National Academy of Sciences; Vol 108 Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2011, 108 (13), pp.5243-5248. ⟨10.1073/pnas.1018692108⟩; (2011-03-29)
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Zugriff:
The human malaria parasite Plasmodium falciparum can cause infected red blood cells (iRBC) to form rosettes with uninfected RBC, a phenotype associated with severe malaria. Rosetting is mediated by a subset of the Plasmodium falciparum membrane protein 1 (PfEMP1) variant adhesins expressed on the infected host-cell surface. Heparin and other sulfated oligosaccharides, however, can disrupt rosettes, suggesting that therapeutic approaches to this form of severe malaria are feasible. We present a structural and functional study of the N-terminal domain of PfEMP1 from the VarO variant comprising the N-terminal segment (NTS) and the first DBL domain (DBL1 α 1 ), which is directly implicated in rosetting. We demonstrate that NTS-DBL1 α 1 -VarO binds to RBC and that heparin inhibits this interaction in a dose-dependent manner, thus mimicking heparin-mediated rosette disruption. We have determined the crystal structure of NTS-DBL1 α 1 , showing that NTS, previously thought to be a structurally independent component of PfEMP1, forms an integral part of the DBL1α domain. Using mutagenesis and docking studies, we have located the heparin-binding site, which includes NTS. NTS, unique to the DBL α-class domain, is thus an intrinsic structural and functional component of the N-terminal VarO domain. The specific interaction observed with heparin opens the way for developing antirosetting therapeutic strategies.
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Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition
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Autor/in / Beteiligte Person: | Baron, Bruno ; Gangnard, Stéphane ; Guillotte, Micheline ; Vigan-Womas, Inès ; Bentley, Graham A. ; Lewit-Bentley, Anita ; Hessel, Audrey ; Mercereau-Puijalon, Odile ; England, Patrick ; Juillerat, Alexandre ; structurale, Immunologie ; Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) ; Immunologie moléculaire des parasites ; Biophysique des macromolécules et de leurs interactions (Plate-forme) ; Institut Pasteur [Paris] (IP) ; Work was supported by the Agence Nationale de la Recherche (contract ANR-07-MIME-021-0), and the 7th European Framework Program (FP7/2007-2013, contract 242095, Evimalar). Fellowships for A.J.were provided by the ANR, Roche Research Foundation, and the Swiss National Science Foundation ; We thank the staff of the ESRF (Grenoble) and SOLEIL (Ile de France), in particular Andrew Thompson, for providing facilities for diffraction measurements and for assistance. We thank H. Lortat-Jacob for gift of heparin. ; ANR-07-MIME-0021,ROSETTE,Analyses sérologiques, fonctionnelles et structurales des facteurs de virulence, PfEMP1, impliqués dans le rosetting et l'auto-agglutinantion(2007) ; European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009) ; Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS) ; Institut Pasteur [Paris] |
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Quelle: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 2011, 108 (13), pp.5243-5248. ⟨10.1073/pnas.1018692108⟩ Proceedings of the National Academy of Sciences; Vol 108 Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2011, 108 (13), pp.5243-5248. ⟨10.1073/pnas.1018692108⟩; (2011-03-29) |
Veröffentlichung: | HAL CCSD, 2011 |
Medientyp: | unknown |
ISSN: | 0027-8424 (print) ; 1091-6490 (print) |
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