The <i>Plasmodium falciparum</i> parasitophorous vacuole protein <scp>P113</scp> interacts with the parasite protein export machinery and maintains normal vacuole architecture

Bullen, Hayley E; Sanders, Paul R; Dans, Madeline G; Jonsdottir, Thorey K; Riglar, David T.; Looker, Oliver; Palmer, Catherine S; Kouskousis, Betty; Charnaud, Sarah C.; Triglia, Tony; Gabriela, Mikha; Schneider, Molly; Chan, Jo‐Anne; Koning-Ward, Tania F de; Baum, Jake; Kazura, James W.; Beeson, James G.; Cowman, Alan F.; Gilson, Paul R.; Crabb, Brendan S.

doi:10.1111/mmi.14904

Cited by 18 publications

(16 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, it has been shown that the protein P113 binds to the N-terminus of PfRh5 and postulated that its glycosylphosphatidylinositol anchor bound the RCR complex to the merozoite membrane 27 . However, recent studies have shown that P113 function was not required for P. falciparum growth and is unlikely to be the membrane anchor for the RCR complex 28 , 29 .…”

Section: Discussionmentioning

confidence: 99%

PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum

et al. 2022

Self Cite

View full text Add to dashboard Cite

The most severe form of malaria is caused by Plasmodium falciparum. These parasites invade human erythrocytes, and an essential step in this process involves the ligand PfRh5, which forms a complex with cysteine-rich protective antigen (CyRPA) and PfRh5-interacting protein (PfRipr) (RCR complex) and binds basigin on the host cell. We identified a heteromeric disulfide-linked complex consisting of P. falciparum Plasmodium thrombospondin-related apical merozoite protein (PfPTRAMP) and P. falciparum cysteine-rich small secreted protein (PfCSS) and have shown that it binds RCR to form a pentameric complex, PCRCR. Using P. falciparum lines with conditional knockouts, invasion inhibitory nanobodies to both PfPTRAMP and PfCSS, and lattice light-sheet microscopy, we show that they are essential for merozoite invasion. The PCRCR complex functions to anchor the contact between merozoite and erythrocyte membranes brought together by strong parasite deformations. We solved the structure of nanobody–PfCSS complexes to identify an inhibitory epitope. Our results define the function of the PCRCR complex and identify invasion neutralizing epitopes providing a roadmap for structure-guided development of these proteins for a blood stage malaria vaccine.

show abstract

Section: Discussionmentioning

confidence: 99%

PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Intriguingly, L1 and L2 adopt the same fold as rhamnose- binding lectins and therefore the same fold as PfP113 29 (Extended Data Fig. 7c), a proposed binding partner of PfRH5 that was previously thought to anchor PfRH5 to the merozoite surface 30 , but which was recently disputed as a surface protein 31 . The large disordered internal loop where PfRIPR is cleaved links L1 and L2.…”

Section: The Structure Of Pfriprmentioning

confidence: 97%

Structure of the PfRCR complex which bridges the malaria parasite and erythrocyte during invasion

Farrell

Alam

Hart

et al. 2023

Preprint

View full text Add to dashboard Cite

The symptoms of malaria occur during the blood stage of infection, when parasites invade and replicate within human erythrocytes. The five-component PfPCRCR complex, containing PfRH5, PfCyRPA, PfRIPR, PfCSS and PfPTRAMP, is essential for erythrocyte invasion by the deadliest human malaria parasite, Plasmodium falciparum. Invasion can be prevented by antibodies or nanobodies against each of these five conserved proteins, making them the leading blood stage malaria vaccine candidates. However, little is known about the molecular mechanism by which PfPCRCR functions during invasion. Here we present the structure of the PfRCR complex, containing PfRH5, PfCyRPA and PfRIPR, determined by cryogenic-electron microscopy. This reveals that PfRIPR consists of an ordered multi-domain core flexibly linked to an elongated tail. We test the hypothesis that PfRH5 opens to insert into the membrane, but instead show that a rigid, disulphide-locked PfRH5 can mediate efficient erythrocyte invasion. Finally, we show that the elongated tail of PfRIPR, which is the target of growth-neutralising antibodies, binds to the PfCSS-PfPTRAMP complex on the parasite membrane. Therefore, a modular PfRIPR is linked to the merozoite membrane through an elongated tail, while its structured core presents PfCyRPA and PfRH5 to interact with erythrocyte receptors. This provides novel insight into the mechanism of erythrocyte invasion and opens the way to new approaches in rational vaccine design.

show abstract

“…Interestingly, even though the 120 aa cargo co-localised with EXP2, it was never observed inside EXP2 loops (Fig 4A, white arrows) which we commonly observe for the exported reporter Hyp1-Nluc-DH upon WR trapping (59,62). These loops are thought to represent accumulated trapped cargo unable to be transported by the PTEX complex at the PVM (59).…”

Section: The Fp2a 120 Aa Reporter Displays Increased Co-localisation ...mentioning

confidence: 77%

PTEX helps efficiently traffic haemoglobinases to the food vacuole inPlasmodium falciparum

Jonsdottir

Elsworth

Cobbold

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

A key element of Plasmodium biology and pathogenesis is the trafficking of ~10% of the parasite proteome into the host red blood cell (RBC) it infects. To cross the parasite-encasing parasitophorous vacuole membrane, exported proteins utilise a channel-containing protein complex termed the Plasmodium translocon of exported proteins (PTEX). PTEX is obligatory for parasite survival, both in vitro and in vivo, suggesting that at least some exported proteins have essential metabolic functions. However, to date only one essential PTEX-dependent process, the new permeability pathway, has been described. To identify other essential PTEX-dependant proteins/processes, we conditionally knocked down the expression of one of its core components, PTEX150, and examined which metabolic pathways were affected. Surprisingly, the food vacuole mediated process of haemoglobin (Hb) digestion was substantially perturbed by PTEX150 knockdown. Using a range of transgenic parasite lines and approaches, we show that two major Hb proteases; falcipain 2a and plasmepsin II, interact with PTEX core components, implicating the translocon's involvement in the trafficking of Hb proteases. We propose a model where these proteases are translocated into the PV via PTEX in order to reach the cytostome, located at the parasite periphery, prior to food vacuole entry. This work offers a another mechanistic explanation for why PTEX function is essential for growth of the parasite within its host RBC.

show abstract

The Plasmodium falciparum parasitophorous vacuole protein P113 interacts with the parasite protein export machinery and maintains normal vacuole architecture

Cited by 18 publications

References 51 publications

PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum

PCRCR complex is essential for invasion of human erythrocytes by Plasmodium falciparum

Structure of the PfRCR complex which bridges the malaria parasite and erythrocyte during invasion

PTEX helps efficiently traffic haemoglobinases to the food vacuole inPlasmodium falciparum

Contact Info

Product

Resources

About