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HDP—A Novel Heme Detoxification Protein from the Malaria Parasite

Jani, Dewal, Nagarkatti, Rana, Beatty, Wandy, Angel, Ross, Slebodnick, Carla, Andersen, John, Kumar, Sanjai, Rathore, Dharmendar·2008·PLoS Pathogens
DOI 10.1371/journal.ppat.1000053PMC PMC2291572
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Figure 1 HDP rapidly detoxifies and sequesters heme as Hz. A, Heme (100 µM) solution was titrated into protein (5 µM) and the heat evolved was measured by Isothermal titration calorimetry. Binding isotherm was generated by integrating the data from the top panel. B, HDP-mediated Hz formation was concentration dependent and occurred rapidly with up to 75% of the total Hz being produced within the first 20 minutes. C, Native HDP (grey) can produce Hz at levels comparable to the recombinant protein (black). D, Powder X-ray diffraction pattern of HDP-produced Hz matches with that of β-hematin. Inset–Scanning electron microscopy image of HDP-produced Hz crystallites that are 0.1–0.2 µm in length (arrows) with a width of approx.0.05 µm (Bar, 0.1 µm) E, Hz formation activity of 0.5 µM P. yoelii HDP (grey bars) is indistinguishable from its P. falciparum ortholog, utilized at identical concentration (black bars). F, Full length HDP (closed circle) is necessary for Hz formation as HDP2 (open circle) and HDP3 (closed triangle) alone could not produce Hz. 0.5 µM of each of the three proteins was utilized for analysis. G, Heme in 2 µM increments was added to a 10 µM solution of either HDP, HDP2, HDP3 or polyhistidine peptide in 100 mM Sodium acetate buffer pH 5.2. Change in absorbance at 414 nm was plotted against the concentration of heme. The curve depicts the non-linear fit of the data. H, HDP-mediated Hz production is restricted to a pH range found inside the FV. I, CQ inhibits HDP-mediated Hz production. Values are mean±s. d
Figure 1 HDP rapidly detoxifies and sequesters heme as Hz. A, Heme (100 µM) solution was titrated into protein (5 µM) and the heat evolved was measured by Isothermal titration calorimetry. Binding isotherm was generated by integrating the data from the top panel. B, HDP-mediated Hz formation was concentration dependent and occurred rapidly with up to 75% of the total Hz being produced within the first 20 minutes. C, Native HDP (grey) can produce Hz at levels comparable to the recombinant protein (black). D, Powder X-ray diffraction pattern of HDP-produced Hz matches with that of β-hematin. Inset–Scanning electron microscopy image of HDP-produced Hz crystallites that are 0.1–0.2 µm in length (arrows) with a width of approx.0.05 µm (Bar, 0.1 µm) E, Hz formation activity of 0.5 µM P. yoelii HDP (grey bars) is indistinguishable from its P. falciparum ortholog, utilized at identical concentration (black bars). F, Full length HDP (closed circle) is necessary for Hz formation as HDP2 (open circle) and HDP3 (closed triangle) alone could not produce Hz. 0.5 µM of each of the three proteins was utilized for analysis. G, Heme in 2 µM increments was added to a 10 µM solution of either HDP, HDP2, HDP3 or polyhistidine peptide in 100 mM Sodium acetate buffer pH 5.2. Change in absorbance at 414 nm was plotted against the concentration of heme. The curve depicts the non-linear fit of the data. H, HDP-mediated Hz production is restricted to a pH range found inside the FV. I, CQ inhibits HDP-mediated Hz production. Values are mean±s. dCC0 · PubMed Central
Figure 2 Structural and biochemical analysis of HDP-mediated Hz formation. A, HDP (Black bars) retained its Hz production activity after heat treatment (Hashed Bars) at 94°C for 10 minutes. B, CD spectra of heat-treated HDP is qualitatively similar to non-treated HDP, which was incubated at room temperature. Mean residue ellipticity is expressed as degree cm−1 dmol−1. C, When compared to MPG (square), MOG (inverted triangle), HRP 2 (diamond) and OA (triangle), HDP (circle) was most effective in producing Hz.
Figure 2 Structural and biochemical analysis of HDP-mediated Hz formation. A, HDP (Black bars) retained its Hz production activity after heat treatment (Hashed Bars) at 94°C for 10 minutes. B, CD spectra of heat-treated HDP is qualitatively similar to non-treated HDP, which was incubated at room temperature. Mean residue ellipticity is expressed as degree cm−1 dmol−1. C, When compared to MPG (square), MOG (inverted triangle), HRP 2 (diamond) and OA (triangle), HDP (circle) was most effective in producing Hz.CC0 · PubMed Central
Figure 3 Circuitous transport and delivery of HDP to the FV. A, HDP is secreted into the cytosol of infected erythrocytes (arrowhead) in early ring stages before any Hz could be detected inside the parasite. B, After secreting it into the host cell cytosol, parasite intakes HDP through the cytostome. C, HDP could be found in transport vesicles destined to the FV. D, Transport vesicles deliver HDP to the FV. E, HDP (arrows) was found in close proximity of Hz crystals. F, HDP (18 nm particles) is transported to FV along with hemoglobin (12 nm particles). Inset G, HDP is being internalized along with hemoglobin. Inset H, Transport vesicle ready to deliver both, HDP and hemoglobin, to the FV. cyt, cytostome; fv, food vacuole; fvm, fv membrane; hz, hemozoin; hdp, heme detoxification protein; hb, hemoglobin; nu, nucleus; par, parasite; ppm, parasite plasma membrane; pvm, parasitophorous vacuole membrane; irbc, infected red blood cell; rbcm, RBC membrane; tv, transport vesicle. Bar, 0.5 µm.
Figure 3 Circuitous transport and delivery of HDP to the FV. A, HDP is secreted into the cytosol of infected erythrocytes (arrowhead) in early ring stages before any Hz could be detected inside the parasite. B, After secreting it into the host cell cytosol, parasite intakes HDP through the cytostome. C, HDP could be found in transport vesicles destined to the FV. D, Transport vesicles deliver HDP to the FV. E, HDP (arrows) was found in close proximity of Hz crystals. F, HDP (18 nm particles) is transported to FV along with hemoglobin (12 nm particles). Inset G, HDP is being internalized along with hemoglobin. Inset H, Transport vesicle ready to deliver both, HDP and hemoglobin, to the FV. cyt, cytostome; fv, food vacuole; fvm, fv membrane; hz, hemozoin; hdp, heme detoxification protein; hb, hemoglobin; nu, nucleus; par, parasite; ppm, parasite plasma membrane; pvm, parasitophorous vacuole membrane; irbc, infected red blood cell; rbcm, RBC membrane; tv, transport vesicle. Bar, 0.5 µm.CC0 · PubMed Central
Figure 4 c-Myc tagged HDP has an identical trafficking pathway to HDP. Panels A–C depicts intracellular location of c-MycHDP fusion protein in parasite-infected RBC. Cytostomal uptake of c-MycHDP (A) followed by its transport (B) and its presence within the FV (C) in close proximity of Hz (shown by arrows). Panels D–F show intracellular location of HDPc-Myc, where, like HDP, chimera was present in the infected RBC cytosol (D), detected in the process of being internalized (D), transported (E), and found in the FV (F), where it presence has been marked with arrows. G, c-Myc antibodies specifically recognized the two chimeras as they did not recognize any protein in the non-transfected 3D7 P. falciparum parasites. H, Schematic representation of the two c-Myc based fusion constructs utilized for expression. I, c-myc tag was still attached to HDP when the protein was secreted out into the infected RBC cytosol. HDP was primarily present as a dimer, with little monomeric form also detected in c-MycHDP preparation. cyt, cytostome; fv, food vacuole; hz, hemozoin; nu, nucleus; irbc, infected red blood cell; tv, transport vesicle. Bar, 0.5 µm
Figure 4 c-Myc tagged HDP has an identical trafficking pathway to HDP. Panels A–C depicts intracellular location of c-MycHDP fusion protein in parasite-infected RBC. Cytostomal uptake of c-MycHDP (A) followed by its transport (B) and its presence within the FV (C) in close proximity of Hz (shown by arrows). Panels D–F show intracellular location of HDPc-Myc, where, like HDP, chimera was present in the infected RBC cytosol (D), detected in the process of being internalized (D), transported (E), and found in the FV (F), where it presence has been marked with arrows. G, c-Myc antibodies specifically recognized the two chimeras as they did not recognize any protein in the non-transfected 3D7 P. falciparum parasites. H, Schematic representation of the two c-Myc based fusion constructs utilized for expression. I, c-myc tag was still attached to HDP when the protein was secreted out into the infected RBC cytosol. HDP was primarily present as a dimer, with little monomeric form also detected in c-MycHDP preparation. cyt, cytostome; fv, food vacuole; hz, hemozoin; nu, nucleus; irbc, infected red blood cell; tv, transport vesicle. Bar, 0.5 µmCC0 · PubMed Central
Figure 5 Genetic manipulation of HDP locus. Schematic representation of the strategy used for targeting HDP locus through single cross over recombination. A, Schematic representation of the plasmid and the genomic locus showing the enzyme sites and the genes flanking HDP. The anticipated cross-over event at the HDP locus and restriction enzyme sites for Eco RV, E and Bam HI, B are shown. Eco RV site is unique to the parasite DNA while Bam HI site is unique to the plasmid. B, Lanes 1 and 2, depict Bam HI-linearized pHDPKO (6.3 kb) and Eco RV and Bam HI digested DNA from wild type P. falciparum parasites containing the HDP locus (5.3 kb), respectively. Lanes 3 and 4 depict the transfected parasites after 2nd and 3rd drug cycle, respectively. Parasites surviving after three selection cycles (lanes 3, 4) had an intact HDP locus and an episomal copy of the pHDPKO plasmid expressing hDHFR. The expected size on integration is indicated by the arrow (6657 bp). C, Immuno-fluorescence staining using anti-HDP antibodies showed that the transfected parasites continually expressed HDP (green) even after the third drug cycle thus indicating that the locus was not disrupted. Arrows on the DIC image indicate hemozoin. Parasite nucleus (blue) is stained with DAPI.
Figure 5 Genetic manipulation of HDP locus. Schematic representation of the strategy used for targeting HDP locus through single cross over recombination. A, Schematic representation of the plasmid and the genomic locus showing the enzyme sites and the genes flanking HDP. The anticipated cross-over event at the HDP locus and restriction enzyme sites for Eco RV, E and Bam HI, B are shown. Eco RV site is unique to the parasite DNA while Bam HI site is unique to the plasmid. B, Lanes 1 and 2, depict Bam HI-linearized pHDPKO (6.3 kb) and Eco RV and Bam HI digested DNA from wild type P. falciparum parasites containing the HDP locus (5.3 kb), respectively. Lanes 3 and 4 depict the transfected parasites after 2nd and 3rd drug cycle, respectively. Parasites surviving after three selection cycles (lanes 3, 4) had an intact HDP locus and an episomal copy of the pHDPKO plasmid expressing hDHFR. The expected size on integration is indicated by the arrow (6657 bp). C, Immuno-fluorescence staining using anti-HDP antibodies showed that the transfected parasites continually expressed HDP (green) even after the third drug cycle thus indicating that the locus was not disrupted. Arrows on the DIC image indicate hemozoin. Parasite nucleus (blue) is stained with DAPI.CC0 · PubMed Central
Figure 6 Non-specific recombination of HDP-YFP chimera. A, Schematic representation of the gene replacement strategy employed for obtaining HDP knocked-in parasites. The anticipated cross-over event at the HDP locus and the restriction enzyme sites for Eco RV, E and Xho I, X are shown. B, Lanes 1 and 2 depict Xho I linearized pHDP-YFP (6.32 kb) and Xho I and Eco RV digested DNA from wild type P. falciparum parasites containing the HDP locus (5.3kb), respectively. Lane 3 depicts the double digested DNA from transfected parasites after the 3rd drug cycle. Integration at non specific sites was observed as seen by higher size bands in comparison to the episomal plasmid, represented by the open arrows. As the genomic DNA was digested with restriction enzymes unique to the flanking regions of the HDP locus (Eco RV) and the plasmid (Xho I) these bands do not appear to be site specific integrations of concatameric forms of pHDP-YFP. No integration was observed at the expected size as indicated by the arrow at 7588 bp. Parasites surviving after three selection cycles (lane 3) had the non-recombined HDP locus and no YFP expression, as determined by fluorescence microscopy. C, Immuno-fluorescence staining of these parasites with anti HDP antibodies also indicated the expression of the native HDP (green) after the third drug cycle. Arrows on the DIC image indicate hemozoin. Parasite nucleus (blue) is stained with DAPI.
Figure 6 Non-specific recombination of HDP-YFP chimera. A, Schematic representation of the gene replacement strategy employed for obtaining HDP knocked-in parasites. The anticipated cross-over event at the HDP locus and the restriction enzyme sites for Eco RV, E and Xho I, X are shown. B, Lanes 1 and 2 depict Xho I linearized pHDP-YFP (6.32 kb) and Xho I and Eco RV digested DNA from wild type P. falciparum parasites containing the HDP locus (5.3kb), respectively. Lane 3 depicts the double digested DNA from transfected parasites after the 3rd drug cycle. Integration at non specific sites was observed as seen by higher size bands in comparison to the episomal plasmid, represented by the open arrows. As the genomic DNA was digested with restriction enzymes unique to the flanking regions of the HDP locus (Eco RV) and the plasmid (Xho I) these bands do not appear to be site specific integrations of concatameric forms of pHDP-YFP. No integration was observed at the expected size as indicated by the arrow at 7588 bp. Parasites surviving after three selection cycles (lane 3) had the non-recombined HDP locus and no YFP expression, as determined by fluorescence microscopy. C, Immuno-fluorescence staining of these parasites with anti HDP antibodies also indicated the expression of the native HDP (green) after the third drug cycle. Arrows on the DIC image indicate hemozoin. Parasite nucleus (blue) is stained with DAPI.CC0 · PubMed Central
Figure 7 Episomal expression of the YFP-based chimera. P. falciparum 3D7 parasites were independently transfected with plasmids pHDP-YFP (A), pYFP-HDP (C) and pYFP (E) containing the hDHFR cassette as selection marker. Culture was maintained in the presence of WR92210 and the expression of yellow fluorescent protein was investigated by live cell imaging. On expression, transport of both the fusion proteins was found to be disrupted (B and D) with protein exclusively localized within the parasite cytosol. pYFP, when expressed alone (F) showed YFP, like GFP [50], to be localized within the parasite.
Figure 7 Episomal expression of the YFP-based chimera. P. falciparum 3D7 parasites were independently transfected with plasmids pHDP-YFP (A), pYFP-HDP (C) and pYFP (E) containing the hDHFR cassette as selection marker. Culture was maintained in the presence of WR92210 and the expression of yellow fluorescent protein was investigated by live cell imaging. On expression, transport of both the fusion proteins was found to be disrupted (B and D) with protein exclusively localized within the parasite cytosol. pYFP, when expressed alone (F) showed YFP, like GFP [50], to be localized within the parasite.CC0 · PubMed Central

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Authors
Jani, D., Nagarkatti, R., Beatty, W., Angel, R., Slebodnick, C., Andersen, J., Kumar, S., & Rathore, D.
Venue
PLoS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2008-04-25
Volume
4
Issue
4
Pages
e1000053
ISSN
1553-7374
DOI
10.1371/journal.ppat.1000053
PMC
PMC2291572
Cited by
166
References
0
Language
en
Licence
creativecommons.org/publicdomain/zero/1.0/ (unspecified)

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Jani, D., Nagarkatti, R., Beatty, W., Angel, R., Slebodnick, C., Andersen, J., Kumar, S., & Rathore, D. (2008). HDP—A Novel Heme Detoxification Protein from the Malaria Parasite. PLoS Pathogens. https://doi.org/10.1371/journal.ppat.1000053