Plasmodium falciparum: Mapping the Membrane-Binding Domain in the Ring-Infected Erythrocyte Surface Antigen

Foley, Michael; Corcoran, Lynn M.; Tilley, Leann; Rf, Anders

doi:10.1006/expr.1994.1096

Cited by 30 publications

(26 citation statements)

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“…The functional role of these repeats is not clear. It is interesting to note that the binding regions of MESA, RESA and MSP-1 mentioned above are all found in non-repetitive domains (33)(34)(35). Previous work that mapped the spectrin-binding domain of KAHRP to a 271-residue region (27), and this region contained the 5Ј-repeat.…”

Section: Discussionmentioning

confidence: 93%

Structural and Functional Studies of Interaction between Plasmodium falciparum Knob-associated Histidine-rich Protein (KAHRP) and Erythrocyte Spectrin

Pei

Guo

et al. 2005

Journal of Biological Chemistry

109

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Plasmodium falciparum dramatically modifies the structure and function of the membrane of the parasitized host erythrocyte. Altered membrane properties are the consequence of the interaction of a group of exported malaria proteins with host cell membrane proteins. KAHRP (the knob-associated histidine-rich protein), a member of this group, has been shown to interact with erythrocyte membrane skeletal protein spectrin. However, the molecular basis for this interaction has yet to be defined. In the present study, we defined the binding motifs in both KAHRP and spectrin and identified a functional role for this interaction. We showed that spectrin bound to a 72-amino-acid KAHRP fragment (residues 370 -441). Among nine-spectrin fragments, which encompass the entire ␣ and ␤ spectrin molecules (four ␣ spectrin and five ␤ spectrin fragments), KAHRP bound only to one, the ␣ N-5 fragment. The KAHRP-binding site within the ␣ N-5 fragment was localized uniquely to repeat 4. The interaction of fulllength spectrin dimer to KAHRP was inhibited by repeat 4 of ␣ spectrin. Importantly, resealing of this repeat peptide into erythrocytes mislocalized KAHRP in the parasitized cells. We concluded that the interaction of KAHRP with spectrin is critical for appropriate membrane localization of KAHRP in parasitized erythrocytes. As the presence of KAHRP at the erythrocyte membrane is necessary for cytoadherence in vivo, our findings have implications for the development of new therapies for mitigating the severity of malaria infection.Malaria caused by Plasmodium falciparum is the most serious parasitic disease of humans. Clinical symptoms occur during the asexual stage of the life cycle of the parasites, at which time it multiplies within the human erythrocyte. During intraerythrocytic growth, the parasite extensively modifies the host erythrocyte resulting in alterations of morphology, mechanical properties, and adhesive properties. It is generally believed that almost all the altered properties of parasitized erythrocytes are because of the action of a group of parasite proteins that become associated with erythrocyte membrane proteins (see Refs. 1-3 for recent reviews). Well studied members of this group include the knob-associated histidine-rich protein (KAHRP), 1 P. falciparum erythrocyte membrane protein 1 (PfEMP1), the ring parasite-infected erythrocyte surface antigen (RESA), and the mature parasite-infected erythrocyte surface antigen (MESA).KAHRP, an 85-105-kDa protein that is expressed during the middle and later stages of the asexual cycle (4, 5), has been shown to be critically important for knob formation in infected erythrocytes (6). It interacts with erythrocyte skeletal proteins such as spectrin, actin, and ankyrin (7, 8) and also with erythrocyte membrane-associated parasite protein, PfEMP1 (9). PfEMP1 mediates the adhesion of parasitized erythrocytes to the vascular endothelium (10), a process strongly implicated in the pathology of cerebral malaria (11). The absence of the KAHRP protein at the erythrocyte membrane l...

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Section: Discussionmentioning

confidence: 93%

Structural and Functional Studies of Interaction between Plasmodium falciparum Knob-associated Histidine-rich Protein (KAHRP) and Erythrocyte Spectrin

Pei

Guo

et al. 2005

Journal of Biological Chemistry

109

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“…Here it remains as a soluble protein, unlike other exported type IV HSP40 proteins such as MESA and RESA, which bind to components of the RBC cytoskeleton (8,28,35,36,74,89). Several P. falciparum genes are predicted to be soluble exported proteins, but only a small subset of these are known to reside freely in the RBC cytoplasm, including HRP2 and REX3 (58).…”

Section: Discussionmentioning

confidence: 99%

“…Mature erythrocyte surface antigen (MESA) (PFE0040c) is exported to the RBC surface, where it interacts with protein 4.1 of the cytoskeleton to potentially facilitate RBC remodeling (8,11,23,89). Ring erythrocyte surface antigen (RESA) (PFA0110w) is similarly localized to the RBC membrane, binds to spectrin, and is suggested to both participate in cytoadhesion and stabilize the cytoskeleton against heat shock (21,24,27,28,35,36,74,78). Targeted disruption of the type IV HSP40 PF10_0381 resulted in decreased knobs (59), which are protrusions of the RBC membrane comprised mainly of knob-associated histidine-rich protein (KAHRP) (82).…”

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confidence: 99%

Functional Analysis of the Exported Type IV HSP40 Protein PfGECO in Plasmodium falciparum Gametocytes

et al. 2011

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During Plasmodium falciparum infection, host red blood cell (RBC) remodeling is required for the parasite's survival. Such modifications are mediated by the export of parasite proteins into the RBC that alter the architecture of the RBC membrane and enable cytoadherence. It is probable that some exported proteins also play a protective role against the host defense response. This may be of particular importance for the gametocyte stage of the life cycle that is responsible for malaria transmission, since the gametocyte remains in contact with blood as it proceeds through five morphological stages (I to V) during its 12-day maturation. Using microarray analysis, we identified several genes with encoded secretory or export sequences that were differentially expressed during early gametocytogenesis. One of these, PfGECO, encodes a predicted type IV heat shock protein 40 (HSP40) that we show is expressed in gametocyte stages I to IV and is exported to the RBC cytoplasm. HSPs are traditionally induced under stressful conditions to maintain homeostasis, but PfGECO expression was not increased upon heat shock, suggesting an alternate function. Targeted disruption of PfGECO indicated that the gene is not essential for gametocytogenesis in vitro, and quantitative reverse transcriptase PCR (RT-PCR) showed that there was no compensatory expression of the other type IV HSP40 genes. Although P. falciparum HSP40 members are implicated in the trafficking of proteins to the RBC surface, removal of PfGECO did not affect the targeting of other exported gametocyte proteins. This work has expanded the repertoire of known gametocyte-exported proteins to include a type IV HSP40, PfGECO.

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“…Altered deformability during the ring stage is most probably a consequence of the attachment of RESA to spectrin (23). Binding of RESA to ␤1R16 spectrin structural repeat close to the interaction region between ␣1 and ␤1 spectrins significantly increases the stability of spectrin tetramers (24).…”

Section: Discussionmentioning

confidence: 99%

Effect of plasmodial RESA protein on deformability of human red blood cells harboring Plasmodium falciparum

Mills¹,

Diez-Silva

Quinn

et al. 2007

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

178

166

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During intraerythrocytic development, Plasmodium falciparum exports proteins that interact with the host cell plasma membrane and subplasma membrane-associated spectrin network. Parasiteexported proteins modify mechanical properties of host RBCs, resulting in altered cell circulation. In this work, optical tweezers experiments of cell mechanical properties at normal physiological and febrile temperatures are coupled, for the first time, with targeted gene disruption techniques to measure the effect of a single parasite-exported protein on host RBC deformability. We investigate Pf155/Ring-infected erythrocyte surface antigen (RESA), a parasite protein transported to the host spectrin network, on deformability of ring-stage parasite-harboring human RBCs. Using a set of parental, gene-disrupted, and revertant isogenic clones, we found that RESA plays a major role in reducing deformability of host cells at the early ring stage of parasite development, but not at more advanced stage. We also show that the effect of RESA on deformability is more pronounced at febrile temperature, which ring-stage parasite-harboring RBCs can be exposed to during a malaria attack, than at normal body temperature. malaria ͉ erythrocyte ͉ membrane shear modulus ͉ spectrin ͉ cytoskeleton A fter Plasmodium falciparum merozoite invasion of a human RBC, the parasite differentiates and multiplies for 48 h, leading to rupture of the parasitized RBC (Pf-RBCs) and release of new merozoites in the blood circulation. Throughout this 48-h period, several parasite proteins are introduced into the RBC plasma membrane and submembranous protein skeleton, thereby modifying a range of structural and functional properties of the Pf-RBCs (1-4). The best documented changes occur as P. falciparum matures to the trophozoite (24-36 h) and schizont (36-48 h) stages, when Pf-RBCs display decreased membrane deformability (2-6), become spherical, and develop cytoadherence properties responsible for parasite sequestration in the postcapillary venules of different organs (7,8). In contrast, during early parasite development, ring-stage (0-24 h after invasion) Pf-RBCs preserve their biconcave shape, can circulate in peripheral blood (9), and thus are exposed to the spleen red pulp. Ring-stage Pf-RBCs may pass through this spleen compartment, be expelled from circulation, or return to the circulation once the parasite has been removed (10). Although the relative importance of these different processes and their underlying mechanisms are not fully understood, it is likely that altered deformability of ring-stage Pf-RBCs (11) plays a crucial role in determining Pf-RBCs spleen processing.Introduction of parasite components within the Pf-RBC membrane and cortical cytoskeleton begins soon after RBC invasion, as demonstrated for the well characterized parasite protein Pf155/Ring-infected erythrocyte surface antigen (RESA) (12). This protein is discharged by the invading merozoite and exported to the Pf-RBC membrane where, once phosphorylated, it interacts with the spectrin n...

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Plasmodium falciparum: Mapping the Membrane-Binding Domain in the Ring-Infected Erythrocyte Surface Antigen

Cited by 30 publications

References 0 publications

Structural and Functional Studies of Interaction between Plasmodium falciparum Knob-associated Histidine-rich Protein (KAHRP) and Erythrocyte Spectrin

Structural and Functional Studies of Interaction between Plasmodium falciparum Knob-associated Histidine-rich Protein (KAHRP) and Erythrocyte Spectrin

Functional Analysis of the Exported Type IV HSP40 Protein PfGECO in Plasmodium falciparum Gametocytes

Effect of plasmodial RESA protein on deformability of human red blood cells harboring Plasmodium falciparum

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