Structural and regulatory insights into the glideosome-associated connector from Toxoplasma gondii
- Imperial College London, United Kingdom
- University of Geneva, Switzerland
- Aarhus University, Denmark
Abstract
The phylum of Apicomplexa groups intracellular parasites that employ substrate-dependent gliding motility to invade host cells, egress from the infected cells and cross biological barriers. The glideosome associated connector (GAC) is a conserved protein essential to this process. GAC facilitates the association of actin filaments with surface transmembrane adhesins and the efficient transmission of the force generated by myosin translocation of actin to the cell surface substrate. Here, we present the crystal structure of Toxoplasma gondii GAC and reveal a unique, supercoiled armadillo repeat region that adopts a closed ring conformation. Characterisation of the solution properties together with membrane and F-actin binding interfaces suggest that GAC adopts several conformations from closed to open and extended. A multi-conformational model for assembly and regulation of GAC within the glideosome is proposed.
Data availability
Diffraction data have been deposited in PDB under the accession code 8C4A.The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD039335.All data generated or analysed during this study are included in the manuscript, figures and supplementary files.
Article and author information
Author details
Nicolas Dos Santos Pacheco
Helena Ø Rasmussen
Dominique Soldati-Favre
Funding
Leverhulme Trust (RPG_2018_107)
- Stephen Matthews
Biotechnology and Biological Sciences Research Council (BB/W001764/1)
- Stephen Matthews
Swiss Re Foundation (10030_185325)
- Dominique Soldati-Favre
Swiss Re Foundation (CRSII5_198545)
- Dominique Soldati-Favre
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Kumar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structural and regulatory insights into the glideosome-associated connector from Toxoplasma gondii
eLife 12:e86049.
https://doi.org/10.7554/eLife.86049
Further reading
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- Microbiology and Infectious Disease
Apicomplexan parasites balance proliferation, persistence, and spread in their metazoan hosts. AGC kinases, such as PKG, PKA, and the PDK1 ortholog SPARK, integrate environmental signals to toggle parasites between replicative and motile life stages. Recent studies have cataloged pathways downstream of apicomplexan PKG and PKA; however, less is known about the global integration of AGC kinase signaling cascades. Here, conditional genetics coupled to unbiased proteomics demonstrates that SPARK complexes with an elongin-like protein to regulate the stability of PKA and PKG in the model apicomplexan Toxoplasma gondii. Defects attributed to SPARK depletion develop after PKG and PKA are down-regulated. Parasites lacking SPARK differentiate into the chronic form of infection, which may arise from reduced activity of a coccidian-specific PKA ortholog. This work delineates the signaling topology of AGC kinases that together control transitions within the asexual cycle of this important family of parasites.
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- Immunology and Inflammation
- Microbiology and Infectious Disease
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