2XU0

Crystal structure of the NTS-DBL1(alpha-1) domain of the Plasmodium falciparum membrane protein 1 (PfEMP1) from the varO strain.

Summary for 2XU0

• Entry DOI: 10.2210/pdb2xu0/pdb
• Descriptor: ERYTHROCYTE MEMBRANE PROTEIN 1, PROLINE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: membrane protein, adhesion, virulence, duffy-binding-like-domain
• Biological source: PLASMODIUM FALCIPARUM PALO ALTO/UGANDA
• Total number of polymer chains: 1
• Total formula weight: 56921.83

Authors

Juillerat, A.,Lewit-Bentley, A.,Guillotte, M.,Vigan-Womas, I.,Hessler, A.,Gangnard, S.,England, P.,Mercereau-Puijalon, O.,Bentley, G.A. (deposition date: 2010-10-14, release date: 2011-04-06, Last modification date: 2024-10-23)

Primary citation

Juillerat, A.,Lewit-Bentley, A.,Guillotte, M.,Gangnard, S.,Hessel, A.,Baron, B.,Vigan-Womas, I.,England, P.,Mercereau-Puijalon, O.,Bentley, G.A.
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.USA, 108:5243-, 2011

PubMed Abstract: 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.

PubMed: 21402930
DOI: 10.1073/PNAS.1018692108

Experimental method

X-RAY DIFFRACTION (2.06 Å)