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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.
Proc Natl Acad Sci U S A ; 108(13): 5243-8, 2011 Mar 29.
Article em En | MEDLINE | ID: mdl-21402930
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 (DBL1α(1)), which is directly implicated in rosetting. We demonstrate that NTS-DBL1α(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-DBL1α(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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Formação de Roseta / Heparina / Proteínas de Protozoários / Estrutura Terciária de Proteína / Eritrócitos Limite: Humans Idioma: En Ano de publicação: 2011 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Plasmodium falciparum / Formação de Roseta / Heparina / Proteínas de Protozoários / Estrutura Terciária de Proteína / Eritrócitos Limite: Humans Idioma: En Ano de publicação: 2011 Tipo de documento: Article