Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets
Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis of Plasmodium falciparum rely on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a fir...
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doaj-b65c35d6ff964fcd82d2f940374cef222021-05-05T21:36:11ZengeLife Sciences Publications LtdeLife2050-084X2020-10-01910.7554/eLife.60581Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targetsDihia Moussaoui0https://orcid.org/0000-0002-1605-9619James P Robblee1Daniel Auguin2Elena B Krementsova3Silvia Haase4Thomas CA Blake5https://orcid.org/0000-0002-8534-0025Jake Baum6https://orcid.org/0000-0002-0275-352XJulien Robert-Paganin7https://orcid.org/0000-0001-6102-2025Kathleen M Trybus8https://orcid.org/0000-0002-5583-8500Anne Houdusse9https://orcid.org/0000-0002-8566-0336Structural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, Paris, FranceDepartment of Molecular Physiology and Biophysics, University of Vermont, Burlington, United StatesLaboratoire de Biologie des Ligneux et des Grandes Cultures (LBLGC), Université d’Orléans, INRAE, USC1328, Orléans, FranceDepartment of Molecular Physiology and Biophysics, University of Vermont, Burlington, United StatesDepartment of Life Sciences, Imperial College London, South Kensington, London, United KingdomDepartment of Life Sciences, Imperial College London, South Kensington, London, United KingdomDepartment of Life Sciences, Imperial College London, South Kensington, London, United KingdomStructural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, Paris, FranceDepartment of Molecular Physiology and Biophysics, University of Vermont, Burlington, United StatesStructural Motility, Institut Curie, Paris Université Sciences et Lettres, Sorbonne Université, CNRS UMR144, Paris, FranceParasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis of Plasmodium falciparum rely on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here, we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future anti-malarials targeting both the glideosome motor and its regulatory elements.https://elifesciences.org/articles/60581malariamliding motilityerythrocytes invasionmyosin APfELCantimalarial drugs |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dihia Moussaoui James P Robblee Daniel Auguin Elena B Krementsova Silvia Haase Thomas CA Blake Jake Baum Julien Robert-Paganin Kathleen M Trybus Anne Houdusse |
spellingShingle |
Dihia Moussaoui James P Robblee Daniel Auguin Elena B Krementsova Silvia Haase Thomas CA Blake Jake Baum Julien Robert-Paganin Kathleen M Trybus Anne Houdusse Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets eLife malaria mliding motility erythrocytes invasion myosin A PfELC antimalarial drugs |
author_facet |
Dihia Moussaoui James P Robblee Daniel Auguin Elena B Krementsova Silvia Haase Thomas CA Blake Jake Baum Julien Robert-Paganin Kathleen M Trybus Anne Houdusse |
author_sort |
Dihia Moussaoui |
title |
Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets |
title_short |
Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets |
title_full |
Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets |
title_fullStr |
Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets |
title_full_unstemmed |
Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets |
title_sort |
full-length plasmodium falciparum myosin a and essential light chain pfelc structures provide new anti-malarial targets |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2020-10-01 |
description |
Parasites from the genus Plasmodium are the causative agents of malaria. The mobility, infectivity, and ultimately pathogenesis of Plasmodium falciparum rely on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here, we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future anti-malarials targeting both the glideosome motor and its regulatory elements. |
topic |
malaria mliding motility erythrocytes invasion myosin A PfELC antimalarial drugs |
url |
https://elifesciences.org/articles/60581 |
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