Linked Life Data

21402930

Source:http://linkedlifedata.com/resource/pubmed/id/21402930

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2011-3-30
pubmed:databankReference
pubmed:abstractText
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?(1)), which is directly implicated in rosetting. We demonstrate that NTS-DBL1?(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?(1), showing that NTS, previously thought to be a structurally independent component of PfEMP1, forms an integral part of the DBL1? domain. Using mutagenesis and docking studies, we have located the heparin-binding site, which includes NTS. NTS, unique to the DBL ?-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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1091-6490
pubmed:author
pubmed:issnType
Electronic
pubmed:day
29
pubmed:volume
108
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5243-8
pubmed:dateRevised
2011-9-30
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Structure of a Plasmodium falciparum PfEMP1 rosetting domain reveals a role for the N-terminal segment in heparin-mediated rosette inhibition.
pubmed:affiliation
Institut Pasteur, Unité d'Immunologie Structurale, 75015 Paris, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't