Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets.

Dihia Moussaoui,James P Robblee,Elena B Krementsova,Daniel Auguin,Kathleen M Trybus,Thomas Ca Blake,Silvia Haase,Jake Baum,Anne Houdusse,Julien Robert-Paganin

doi:10.7554/elife.60581

Abstract

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.

Highlights

Parasites from the genus Plasmodium, the causative agents of malaria, are responsible for half of a million deaths per year (WHO, 2018)
The electron density was well-defined for the motor domain and the lever arm, in Figure 1 continued membrane (HPM)
The orientation of the converter and lever arm differs in these two states. (d) The lever arm has been built in these two states of the motor, revealing the structure of the two bound light chains, PfELC and MTIP, displayed here in a similar orientation

Summary

Introduction

Parasites from the genus Plasmodium, the causative agents of malaria, are responsible for half of a million deaths per year (WHO, 2018). The global death rate from malaria has recently started to rise after many years of decrease (WHO, 2018), emphasizing the necessity to develop new interventions, because climate change may further expand the range of Anopheles mosquitoes (Hertig, 2019; Ryan et al, 2020). Locomotion of apicomplexan parasites occurs by a process called gliding motility (reviewed in Frenal et al, 2017). This mode of displacement and the infectivity of the parasite rely on a macromolecular assembly called the glideosome that is anchored in an inner membrane complex located ~25 nm below the parasite plasma membrane (PPM).

Methods

Results

Conclusion