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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Main Authors:	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
Format:	Online
Language:	English
Published:	Federation of American Societies for Experimental Biology 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202109/

id	pubmed-4202109
recordtype	oai_dc
spelling	pubmed-42021092014-11-03 A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface 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 Research Communications 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 subtelomeric (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. Federation of American Societies for Experimental Biology 2014-10 /pmc/articles/PMC4202109/ /pubmed/24983468 http://dx.doi.org/10.1096/fj.14-256057 Text en © FASEB This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) (http://creativecommons.org/licenses/by-nc/4.0/) which permits noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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
spellingShingle	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 A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface
author_facet	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
author_sort	Oberli, Alexander
title	A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface
title_short	A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface
title_full	A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface
title_fullStr	A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface
title_full_unstemmed	A Plasmodium falciparum PHIST protein binds the virulence factor PfEMP1 and comigrates to knobs on the host cell surface
title_sort	plasmodium falciparum phist protein binds the virulence factor pfemp1 and comigrates to knobs on the host cell surface
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 subtelomeric (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.
publisher	Federation of American Societies for Experimental Biology
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202109/
_version_	1613146385705598976

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

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