# Structure and function of the Plasmodium myosin XIV-actin glideosome

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $710,260

## Abstract

Malaria is a blood-borne disease caused by apicomplexan parasites of the genus Plasmodium, which
causes more than a half million deaths per year. The life cycle alternates between a mosquito and a
human stage; in the latter stage merozoites invade red blood cells, a process that occurs in seconds.
Invasion into and egress from an infected host cell are powered by a multi-protein assembly called the
glideosome, the core of which is the class XIV myosin motor PfMyoA, making it a primary target against
malaria. This motor is anchored via its light chain subunit MTIP (myosin tail interacting protein) to integral
membrane proteins in a double-membraned flattened complex called the inner membrane complex
(IMC), which lies ~25nm below the plasma membrane. The Plasmodium actin isoform (PfAct1) that
interacts with PfMyoA is quite divergent in sequence from, and much more dynamic than, muscle actin.
Despite the importance of the parasite motor, knowledge of its structure, function, and regulation has
been limited primarily because PfMyoA to date has not been expressed in a heterologous system. The
Trybus laboratory has, however, recently discovered how to express milligram quantities of this motor
using the baculovirus/insect cell expression system. They have also expressed Plasmodium actin, which
allows actomyosin interactions to be studied with native isoforms. The Plasmodium motor and actin will
be characterized by a combination of state-of-the-art biochemical, biophysical, and high resolution
structural biological techniques. This is a multiple PI R01 grant: Trybus (protein expression,
biochemical/biophysical assays of Plasmodium myosin and actin, University of Vermont), Anne
Houdusse (crystallography, Institute Curie) and Dorit Hanein and Niels Volkmann (high resolution cryo-
electron microscopy and image reconstruction, Sanford Burnham Prebys Institute). In Aim 1 we will
determine how PfMyoA motor activity is regulated in the glideosome, and the mechanism by which small
molecules inhibit activity. Unloaded and loaded ensemble in vitro motility assays and transient kinetics
will be used to assess function. The goal of Aim 2 is to crystallize the Plasmodium falciparum class XIV
myosin for structure-function studies, and to determine the site of binding of small molecule inhibitors.
Aim 3 seeks to understand how the unique properties of Plasmodium actin and its interaction with
Plasmodium actin-binding proteins regulate actin dynamics and affect its ability to interact with PfMyoA.
In Aim 4 we will determine the structure of Plasmodium actin filaments, alone or decorated with PfMyoA,
at 5Å resolution or better by high-resolution cryo-electron microscopy. Taken together, these studies will
establish the molecular basis for Plasmodium glideosome activity.

## Key facts

- **NIH application ID:** 10153690
- **Project number:** 5R01AI132378-05
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** ANNE HOUDUSSE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $710,260
- **Award type:** 5
- **Project period:** 2017-05-11 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153690

## Citation

> US National Institutes of Health, RePORTER application 10153690, Structure and function of the Plasmodium myosin XIV-actin glideosome (5R01AI132378-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10153690. Licensed CC0.

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