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Structural studies of the Apicomplexan glideosome-associated connector platform

Reference	BB/W001764/1
Principal Investigator / Supervisor	Professor Steve Matthews
Co-Investigators / Co-Supervisors
Institution	Imperial College London
Department	Life Sciences
Funding type	Research
Value (£)	543,935
Status	Current
Type	Research Grant
Start date	01/01/2023
End date	31/12/2025
Duration	36 months

Abstract

Apicomplexan parasites are etiological agents of some major diseases and are a global threat to human and animal health, with the most significant being malaria (Plasmodium), cryptosporidiosis (Cryptosporidium), coccidiosis (Eimeria) and toxoplasmosis (Toxoplasma). The lifestyle of these parasites required extensive periods of parasite motility, which enable colonization, host-cell invasion and subsequent escape (host-cell egress). These processes are essential for parasites survival and the important molecular components in this mechanism are highly conserved. In-depth study of the key factors involved in motility would lead to efficient tools able to prevent parasite replication, such as new vaccine strategies. The field has established a model for parasitic motility in which parasite actin is connected to surface adhesins by a large component within the glideosome, which was recently identified as the glideosome-associated connector (GAC). It bridges the cytoplasmic face of the plasma membrane via interactions with phosphatidic acid-enriched inner leaflet and surface adhesin tails to parasite filamentous actin within the cytoskeleton. This molecular assembly plays a pivotal role in motility, invasion and egress, and is therefore controls the movement and exposure of important surface antigens. Despite the breakthroughs in defining GACs role, an atomic resolution description has yet to be determined. In this new proposal we plan to address this gap and uncover an atomic resolution structural view of the Apicomplexan glideosome-associated connector platform. Our conclusions will provide a foundation for a better understanding of parasite motility and invasion. A comprehensive mechanistic view of the GAC will also shed new light on the dynamics of surface antigens exposure which will be important for effcient vaccine development.

Summary

A parasite grows in a different organism and while it is usually not a benefit to the host, it can often cause disease. The Apicomplexan parasites are single-celled, animal-like organisms which cause a range of diseases in humans and animals. Notably, Plasmodium falciparum is the chief cause of fatal malaria, while. Toxoplasma gondii, one of the world's most common parasites, and is of veterinary and medical importance, as it can cause abortion or congenital disease. It infects humans, wild and domestic animals, including birds, cats, sheep, goats, cattle, pigs and poultry. Toxoplasmosis has an enormous socio-economic and health impacts across the globe. Central to the survival of these parasite is their distinct ability to move (be motile), which allows them to target and invade host cells, live inside and subsequent escape. The molecular strategies that these parasite species employ to enter and escape their target cells are shared. An assembly of proteins form a molecular machine inside the parasite, known as the glideosome. A new protein, the glideosome-associated connector (GAC) has been recently discovered which represents a crucial molecular link between the host cell and the parasite cellular skeleton. This foothold allows the parasite to grip and move with respect to the host cell. This research project aims investigate the molecular shapes and interactions of the glideosome-associated connector (GAC) protein and define the architecture of this multi-component system. This information will help us to see at the atomic level how these parasites can move, and as this process is essential for parasite survival it will provide new guidance for the rational design of new vaccine strategies.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Animal Health, Microbiology, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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