A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface

Uniquely among malaria parasites, Plasmodium falciparum‐infected erythrocytes (iRBCs) develop membrane protrusions, known as knobs, where the parasite adhesion receptor P. falciparum erythrocyte membrane protein 1 (PfEMP1) clusters. Knob formation and the associated iRBC adherence to host endotheliu...

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Veröffentlicht in:The FASEB journal 2014-10, Vol.28 (10), p.4420-4433
Hauptverfasser: Oberli, Alexander, Slater, Leanne M., Cutts, Erin, Brand, Françoise, Mundwiler‐Pachlatko, Esther, Rusch, Sebastian, Masik, Martin F. G., Erat, Michèle C., Beck, Hans‐Peter, Vakonakis, Ioannis
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container_issue 10
container_start_page 4420
container_title The FASEB journal
container_volume 28
creator Oberli, Alexander
Slater, Leanne M.
Cutts, Erin
Brand, Françoise
Mundwiler‐Pachlatko, Esther
Rusch, Sebastian
Masik, Martin F. G.
Erat, Michèle C.
Beck, Hans‐Peter
Vakonakis, Ioannis
description Uniquely among malaria parasites, Plasmodium falciparum‐infected erythrocytes (iRBCs) develop membrane protrusions, known as knobs, where the parasite adhesion receptor P. falciparum erythrocyte membrane protein 1 (PfEMP1) clusters. Knob formation and the associated iRBC adherence to host endothelium are directly linked to the severity of malaria and are functional manifestations of protein export from the parasite to the iRBC. A family of exported proteins featuring Plasmodium helical interspersed sub‐telomeric (PHIST) domains has attracted attention, with members being implicated in host‐parasite protein interactions and differentially regulated in severe disease and among parasite isolates. Here, we show that PHIST member PFE1605w binds the PfEMP1 intracellular segment directly with Kd = 5 ± 0.6 μM, comigrates with PfEMP1 during export, and locates in knobs. PHIST variants that do not locate in knobs (MAL8P1.4) or bind PfEMP1 30 times more weakly (PFI1780w) used as controls did not display the same pattern. We resolved the first crystallographic structure of a PHIST protein and derived a partial model of the PHIST‐PfEMP1 interaction from nuclear magnetic resonance. We propose that PFE1605w reinforces the PfEMP1‐cytoskeletal connection in knobs and discuss the possible role of PHIST proteins as interaction hubs in the parasite exportome.—Oberli, A., Slater, L. M., Cutts, E., Brand, F., Mundwiler‐Pachlatko, E., Rusch, S., Masik, M. F. G., Erat, M. C., Beck, H.‐P., Vakonakis, I. A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface. FASEB J. 28, 4420–4433 (2014). www.fasebj.org
doi_str_mv 10.1096/fj.14-256057
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A family of exported proteins featuring Plasmodium helical interspersed sub‐telomeric (PHIST) domains has attracted attention, with members being implicated in host‐parasite protein interactions and differentially regulated in severe disease and among parasite isolates. Here, we show that PHIST member PFE1605w binds the PfEMP1 intracellular segment directly with Kd = 5 ± 0.6 μM, comigrates with PfEMP1 during export, and locates in knobs. PHIST variants that do not locate in knobs (MAL8P1.4) or bind PfEMP1 30 times more weakly (PFI1780w) used as controls did not display the same pattern. We resolved the first crystallographic structure of a PHIST protein and derived a partial model of the PHIST‐PfEMP1 interaction from nuclear magnetic resonance. We propose that PFE1605w reinforces the PfEMP1‐cytoskeletal connection in knobs and discuss the possible role of PHIST proteins as interaction hubs in the parasite exportome.—Oberli, A., Slater, L. 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A family of exported proteins featuring Plasmodium helical interspersed sub‐telomeric (PHIST) domains has attracted attention, with members being implicated in host‐parasite protein interactions and differentially regulated in severe disease and among parasite isolates. Here, we show that PHIST member PFE1605w binds the PfEMP1 intracellular segment directly with Kd = 5 ± 0.6 μM, comigrates with PfEMP1 during export, and locates in knobs. PHIST variants that do not locate in knobs (MAL8P1.4) or bind PfEMP1 30 times more weakly (PFI1780w) used as controls did not display the same pattern. We resolved the first crystallographic structure of a PHIST protein and derived a partial model of the PHIST‐PfEMP1 interaction from nuclear magnetic resonance. We propose that PFE1605w reinforces the PfEMP1‐cytoskeletal connection in knobs and discuss the possible role of PHIST proteins as interaction hubs in the parasite exportome.—Oberli, A., Slater, L. 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A family of exported proteins featuring Plasmodium helical interspersed sub‐telomeric (PHIST) domains has attracted attention, with members being implicated in host‐parasite protein interactions and differentially regulated in severe disease and among parasite isolates. Here, we show that PHIST member PFE1605w binds the PfEMP1 intracellular segment directly with Kd = 5 ± 0.6 μM, comigrates with PfEMP1 during export, and locates in knobs. PHIST variants that do not locate in knobs (MAL8P1.4) or bind PfEMP1 30 times more weakly (PFI1780w) used as controls did not display the same pattern. We resolved the first crystallographic structure of a PHIST protein and derived a partial model of the PHIST‐PfEMP1 interaction from nuclear magnetic resonance. We propose that PFE1605w reinforces the PfEMP1‐cytoskeletal connection in knobs and discuss the possible role of PHIST proteins as interaction hubs in the parasite exportome.—Oberli, A., Slater, L. M., Cutts, E., Brand, F., Mundwiler‐Pachlatko, E., Rusch, S., Masik, M. F. G., Erat, M. C., Beck, H.‐P., Vakonakis, I. A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface. FASEB J. 28, 4420–4433 (2014). www.fasebj.org</abstract><cop>Bethesda, MD, USA</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>24983468</pmid><doi>10.1096/fj.14-256057</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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subjects Amino Acid Sequence
Carrier Proteins - chemistry
Carrier Proteins - metabolism
Cell Membrane - metabolism
cytoadherence
Erythrocytes - metabolism
Erythrocytes - parasitology
exported proteins
Humans
interactions
malaria
Molecular Sequence Data
Plasmodium falciparum
Plasmodium falciparum - chemistry
Plasmodium falciparum - metabolism
Plasmodium falciparum - pathogenicity
Protein Binding
protein structure
Protein Structure, Tertiary
Protein Transport
Protozoan Proteins - chemistry
Protozoan Proteins - metabolism
Research Communications
title A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface
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