Structural Analysis of the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) Intracellular Domain Reveals a Conserved Interaction Epitope

Mayer, Christina; Slater, Leanne M.; Erat, Michèle C.; Konrat, Robert; Vakonakis, Ioannis

doi:10.1074/jbc.m111.330779

Cited by 54 publications

(87 citation statements)

References 28 publications

(50 reference statements)

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“…PF14_0752 was one of the most highly up-regulated genes in CD36-selected parasites (47), in field isolates (48), and in 3D7 gametocytes (49). Recently a PHISTc family member was shown to bind to the intracellular domain of PfEMP1 (50); however the function of other PHIST family members is unknown and awaits further research.…”

Section: Discussionmentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

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

197

230

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Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We selected three P. falciparum strains (HB3, 3D7, and IT/FCR3) for binding to a human brain endothelial cell line (HBEC-5i). The whole transcriptome of isogenic pairs of selected and unselected parasites was analyzed using a variant surface antigen-supplemented microarray chip. After selection, the most highly and consistently up-regulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7, and ITvar19) that showed 11-to >100-fold increased transcription levels. These var genes encode P. falciparum erythrocyte membrane protein (PfEMP)1 variants with distinct N-terminal domain types (domain cassette 8 or domain cassette 13). Antibodies to HB3var3 and PFD0020c recognized the surface of live IEs and blocked binding to HBEC-5i, thereby confirming the adhesive function of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann-Whitney test, P = 0.029) but not by antibodies from controls with uncomplicated malaria (Mann-Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria.adherence | pathogenesis | sequestration

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Section: Discussionmentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

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

197

230

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“…It confirms the predicted four-alpha-helix structure of the PHIST domain with a very short first alpha helix. The remaining three helices form a three-helix bundle with weak structural similarity to spectrin (19,56). PF3D7_0936800 has been classified as a noncanonical PEXEL protein with the first position of its PEXEL motif rendered from K to R, which was recently shown to be correctly cleaved and Nacetylated, confirming that this PHIST protein is correctly exported from parasites into iRBCs (12).…”

Section: Pf3d7_0532400 (Lymp)mentioning

confidence: 93%

“…The PHIST domain of LyMP (amino acids 122 to 335) interacts with the intracellular acidic terminal segment (ATS) of PfEMP1. Conditional downregulation of LyMP reduced binding to CD36 by Ͼ60%, indicating that the interaction between the PHIST domain of LyMP and the ATS domain of PfEMP1 is important for the cytoadhesive properties of iRBCs (19,38,40,56). A similar conditional downregulation of LyMP in iRBCs preselected for binding to different adhesion receptors displaying different PfEMP1 variants on the surface strongly differed in the reduction of cytoadherence (38), which led to the hypothesis that different PHIST proteins might be responsible for anchoring different PfEMP1 variants to the cytoskeleton.…”

Section: Pf3d7_0532400 (Lymp)mentioning

confidence: 99%

“…Together with the ATS interaction mediated by the LyMP PHIST domain (19), it is evident that LyMP can act as a linker between the virulence complex of P. falciparum PfEMP1 and the host cytoskeleton. PF3D7_0936800 PF3D7_0936800 (PFI1780w) is a PHISTc protein that was also shown to interact with the ATS domain of PfEMP1 albeit much more weakly than LyMP (56). A crystallographic structure of its PHIST domain (residues 85 to 247) has been obtained and is the first available structure for any PHIST protein.…”

Section: Pf3d7_0532400 (Lymp)mentioning

confidence: 99%

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Plasmodium Helical Interspersed Subtelomeric (PHIST) Proteins, at the Center of Host Cell Remodeling

Warncke

Vakonakis

Beck

2016

Microbiol Mol Biol Rev

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SUMMARYDuring the asexual cycle,Plasmodium falciparumextensively remodels the human erythrocyte to make it a suitable host cell. A large number of exported proteins facilitate this remodeling process, which causes erythrocytes to become more rigid, cytoadherent, and permeable for nutrients and metabolic products. Among the exported proteins, a family of 89 proteins, called thePlasmodiumhelical interspersed subtelomeric (PHIST) protein family, has been identified. While also found in otherPlasmodiumspecies, the PHIST family is greatly expanded inP. falciparum. Although a decade has passed since their first description, to date, most PHIST proteins remain uncharacterized and are of unknown function and localization within the host cell, and there are few data on their interactions with other host or parasite proteins. However, over the past few years, PHIST proteins have been mentioned in the literature at an increasing rate owing to their presence at various localizations within the infected erythrocyte. Expression of PHIST proteins has been implicated in molecular and cellular processes such as the surface display of PfEMP1, gametocytogenesis, changes in cell rigidity, and also cerebral and pregnancy-associated malaria. Thus, we conclude that PHIST proteins are central to host cell remodeling, but despite their obvious importance in pathology, PHIST proteins seem to be understudied. Here we review current knowledge, shed light on the definition of PHIST proteins, and discuss these proteins with respect to their localization and probable function. We take into consideration interaction studies, microarray analyses, or data from blood samples from naturally infected patients to combine all available information on this protein family.

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“…These PHISTs cluster into three groups based on their length, distribution, and domains, and at least one member was shown to localize to Maurer's clefts (MAL7P1.172) (11), and others to localize to the erythrocyte membrane [PFI1780w (68) and PFE1605w]. The latter two members seem to directly interact with the ATS domain of PfEMP1 via their PHIST domain (69). Although abundant proteins, no further function has been ascribed, but even less understood are the 17 annotated HYP families.…”

Section: Maurer's Cleft As Sorting Stationsmentioning

confidence: 99%

Maurer's clefts, the enigma of Plasmodium falciparum

Mundwiler-Pachlatko

Beck

2013

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

104

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Plasmodium falciparum, the causative agent of malaria, completely remodels the infected human erythrocyte to acquire nutrients and to evade the immune system. For this process, the parasite exports more than 10% of all its proteins into the host cell cytosol, including the major virulence factor PfEMP1 (P. falciparum erythrocyte surface protein 1). This unusual protein trafficking system involves long-known parasitederived membranous structures in the host cell cytosol, called Maurer's clefts. However, the genesis, role, and function of Maurer's clefts remain elusive. Similarly unclear is how proteins are sorted and how they are transported to and from these structures. Recent years have seen a large increase of knowledge but, as yet, no functional model has been established. In this perspective we review the most important findings and conclude with potential possibilities to shed light into the enigma of Maurer's clefts. Understanding the mechanism and function of these structures, as well as their involvement in protein export in P. falciparum, might lead to innovative control strategies and might give us a handle with which to help to eliminate this deadly parasite.

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Structural Analysis of the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) Intracellular Domain Reveals a Conserved Interaction Epitope

Cited by 54 publications

References 28 publications

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Plasmodium Helical Interspersed Subtelomeric (PHIST) Proteins, at the Center of Host Cell Remodeling

Maurer's clefts, the enigma of Plasmodium falciparum

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