2YK0

Structure of the N-terminal NTS-DBL1-alpha and CIDR-gamma double domain of the PfEMP1 protein from Plasmodium falciparum varO strain.

Summary for 2YK0

• Entry DOI: 10.2210/pdb2yk0/pdb
• Related: 2XU0
• Descriptor: ERYTHROCYTE MEMBRANE PROTEIN 1, MAGNESIUM ION, SULFATE ION, ... (4 entities in total)
• Functional Keywords: adhesin, membrane protein, pfemp1
• Biological source: PLASMODIUM FALCIPARUM
• Total number of polymer chains: 1
• Total formula weight: 92106.42

Authors

Lewit-Bentley, A.,Juillerat, A.,Vigan-Womas, I.,Guillotte, M.,Hessel, A.,Raynal, B.,Mercereau-Puijalon, O.,Bentley, G.A. (deposition date: 2011-05-25, release date: 2012-05-30, Last modification date: 2024-11-13)

Primary citation

Vigan-Womas, I.,Guillotte, M.,Juillerat, A.,Hessel, A.,Raynal, B.,England, P.,Cohen, J.H.,Bertrand, O.,Peyrard, T.,Bentley, G.A.,Lewit-Bentley, A.,Mercereau-Puijalon, O.
Structural Basis for the Abo Blood-Group Dependence of Plasmodium Falciparum Rosetting.
Plos Pathog., 8:2781-, 2012

PubMed Abstract: The ABO blood group influences susceptibility to severe Plasmodium falciparum malaria. Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs. Rosetting is mediated by a subgroup of PfEMP1 adhesins, with RBC binding being assigned to the N-terminal DBL1α₁ domain. Here, we identify the ABO blood group as the main receptor for VarO rosetting, with a marked preference for group A over group B, which in turn is preferred to group O RBCs. We show that recombinant NTS-DBL1α₁ and NTS-DBL1α₁-CIDR1γ reproduce the VarO-iRBC blood group preference and document direct binding to blood group trisaccharides by surface plasmon resonance. More detailed RBC subgroup analysis showed preferred binding to group A₁, weaker binding to groups A₂ and B, and least binding to groups A(x) and O. The 2.8 Å resolution crystal structure of the PfEMP1-VarO Head region, NTS-DBL1α₁-CIDR1γ, reveals extensive contacts between the DBL1α₁ and CIDR1γ and shows that the NTS-DBL1α₁ hinge region is essential for RBC binding. Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα₁. RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins, opening novel opportunities for intervention against severe malaria. By deciphering the structural basis of blood group preferences in rosetting, we provide a link between ABO blood grouppolymorphisms and rosette-forming adhesins, consistent with the selective role of falciparum malaria on human genetic makeup.

PubMed: 22807674
DOI: 10.1371/JOURNAL.PPAT.100278

Experimental method

X-RAY DIFFRACTION (2.8 Å)