Structural insights into diverse modes of ICAM-1 binding by
            <i>Plasmodium falciparum</i>
            -infected erythrocytes

Lennartz, Frank; Smith, C. L.; Craig, Alister G.; Higgins, Matthew K.

doi:10.1073/pnas.1911900116

Cited by 30 publications

(33 citation statements)

References 75 publications

(126 reference statements)

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“…Therefore, while there is no defined sequence motif which characterises the LILRBl- binding RIFINs, mutagenesis shows that they use a shared binding loop and bind through a similar structural mechanism. This is reminiscent of the PfEMPl proteins from Plasmodium falciparum-infected erythrocytes, in which extensive sequence variation is possible, even within a group of surface proteins that bind to the same endothelial receptors, allowing them to maintain function while diversifying to allow antigenic variation and avoidance of immune detection 13 - 15 .…”

mentioning

confidence: 99%

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Harrison

Mørch

Felce

et al. 2020

Nature

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The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur as they replicate within human blood. Despite risking immune detection, the parasite delivers proteins that bind host receptors to infected erythrocyte surfaces. In the causative agent of the most deadly human malaria, Plasmodium falciparum, RIFINs form the largest erythrocyte surface protein family 1 . Some RIFINs can bind inhibitory immune receptors, acting as targets for unusual antibodies containing a LAIR1 ectodomain 2 - 4 , or as ligands for LILRB1 5 . RIFINs stimulate LILRB1 activation and signalling5, thereby potentially dampening human immune responses. To understand this process, we determined a structure of a RIFIN bound to LILRB1. We show that the RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single RIFIN mutation disrupts the complex, blocks LILRB1 binding by all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics NK cell activation by antibody- dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the NK cell immunological synapse and reduce cell activation, as measured by perforin mobilisation. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress NK cell function.

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confidence: 99%

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Harrison

Mørch

Felce

et al. 2020

Nature

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“…2 ). This is reminiscent of the DBL and CIDR domains of Plasmodium parasites, which also have conserved core aromatics and disulfide bonds to stabilize their fold, while showing great diversification on the surface ( 34 – 37 ).…”

Section: Resultsmentioning

confidence: 99%

Structure of the Plasmodium -interspersed repeat proteins of the malaria parasite

Harrison

Reid

Cunningham

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The deadly symptoms of malaria occur as Plasmodium parasites replicate within blood cells. Members of several variant surface protein families are expressed on infected blood cell surfaces. Of these, the largest and most ubiquitous are the Plasmodium-interspersed repeat (PIR) proteins, with more than 1,000 variants in some genomes. Their functions are mysterious, but differential pir gene expression associates with acute or chronic infection in a mouse malaria model. The membership of the PIR superfamily, and whether the family includes Plasmodium falciparum variant surface proteins, such as RIFINs and STEVORs, is controversial. Here we reveal the structure of the extracellular domain of a PIR from Plasmodium chabaudi. We use structure-guided sequence analysis and molecular modeling to show that this fold is found across PIR proteins from mouse- and human-infective malaria parasites. Moreover, we show that RIFINs and STEVORs are not PIRs. This study provides a structure-guided definition of the PIRs and a molecular framework to understand their evolution.

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“…S7). Previously characterized PfEMP1protein receptor interactions are mediated by residues in, or adjacent to, HB1 [24][25][26][27] . Atypical for DBL domains in general, the HB1 helix in VAR2CSA DBL2 is broken up mid-helix by an insertion forming a flexible loop ( Fig.…”

Section: Var2csa-specific Dbl Elements Confer Both Cs Binding and Immmentioning

confidence: 99%

Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

Wang

Dagil

Lavstsen

et al. 2021

Preprint

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Malaria during pregnancy remains a major health problem in Plasmodium falciparum endemic areas. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Placental malaria can have severe consequences for both mother and child by causing maternal anemia, low birth weight and stillbirth. Several VAR2CSA-based vaccines have been developed and clinically tested but they have failed to induce an antibody response that effectively inhibits placental adhesion of different genetic variants of VAR2CSA. The interaction between VAR2CSA and CS represents a unique case of an evolution-driven high-affinity interaction between a protein and an oncofetal carbohydrate. Here, we report cryo-EM structures of the VAR2CSA ectodomain up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations enable rational design of second-generation placental malaria vaccines eliciting broadly VAR2CSA-reactive antibodies and novel cancer therapies.

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Structural insights into diverse modes of ICAM-1 binding by Plasmodium falciparum -infected erythrocytes

Cited by 30 publications

References 75 publications

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Structural basis for RIFIN-mediated activation of LILRB1 in malaria

Structure of the Plasmodium -interspersed repeat proteins of the malaria parasite

Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

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