Scientists shed new light on mechanisms of malaria parasite motility


Date:
October 13, 2020
Source:
eLife
Summary:
New insight on the molecular mechanisms that allow malaria
parasites to move and spread disease within their hosts has just
been published. The first X-ray structures of the molecular complex
that allows malaria parasites to spread disease highlight a novel
target for antimalarial treatments.



FULL STORY ==========================================================================
New insight on the molecular mechanisms that allow malaria parasites to
move and spread disease within their hosts has been published today in
the open- access eLife journal.


==========================================================================
The movement and infectivity of the parasite Plasmodium falciparum,
and ultimately its ability to spread malaria among humans, rely on a
large molecular complex called the glideosome. The new findings provide
a blueprint for the design of future antimalarial treatments that target
both the glideosome motor and the elements that regulate it.

Parasites from the genus Plasmodium, including the deadliest species
Plasmodium falciparum, are responsible for half a million deaths from
malaria each year.

As these parasites are becoming resistant to current artemisinin-based therapies, there are significant efforts to develop new vaccines and
preventive treatments.

"This is especially crucial since climate change threatens to increase
the reach of the Anopheles mosquitoes that carry the parasites," says
lead author Dihia Moussaoui, a PhD student at Institut Curie, Sorbonne University, CNRS, Paris, France. "We wanted to take a deeper look into
the molecular mechanisms that enable these parasites to move among
the cells of their hosts in order to identify potential new targets
for interventions." The core of the glideosome in Plasmodium parasites features an essential Myosin A motor (PfMyoA) -- a primary target for
current drugs against malaria. PfMyoA is a critical molecule in the
parasite life cycle, partly because it powers the fast motility needed
for the parasite's motile spore-like stage. The molecule has a conserved globular motor domain and a lever arm that binds two 'light chains'
of molecules, PfELC and MTIP.

In their study, Moussaoui and the Institut Curie team, in collaboration
with the Trybus laboratory at the University of Vermont, US, captured the
first X- ray structures of the full-length PfMyoA motor in two states
of its motor cycle in Plasmodium falciparum. Their work revealed that
a unique priming of the PfMyoA lever arm results from specific lever
arm/motor domain interactions, allowing for a larger powerstroke to
enhance speed of movement.

The lever arm typically contains amino acid sequences called IQ motifs
that bind molecular light chains. In PfMyoA, both the first IQ motif
and the PfELC that binds to it are so degenerate in their sequence that
the existence of an essential light chain has only been recognised in
recent studies.

Further analysis of the X-ray structures by the team showed that PfELC is essential for the invasion of red blood cells by Plasmodium falciparum
and is a weak link in the assembly of a fully functional glideosome,
providing a second novel target for antimalarials.

"The structures described here provide a precise blueprint for designing
drugs that could target PfELC binding or PfMyoA full-length motor
activity," concludes senior author Anne Houdusse, Team Leader at Institut Curie. "Such treatments would diminish glideosome function, hindering
the motility of Plasmodium parasites at the most infectious stage of
their life cycle and thereby preventing the development of disease."

========================================================================== Story Source: Materials provided by eLife. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. 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, 2020; 9 DOI: 10.7554/eLife.60581 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201013124112.htm

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