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Multivalent interactions drive the Toxoplasma AC9:AC10:ERK7 complex to concentrate ERK7 in the apical cap

View ORCID ProfilePeter S. Back, View ORCID ProfileWilliam J. O’Shaughnessy, View ORCID ProfileAndy S. Moon, View ORCID ProfilePravin S. Dewangan, View ORCID ProfileMichael L. Reese, View ORCID ProfilePeter J. Bradley
doi: https://doi.org/10.1101/2022.01.04.474968
Peter S. Back
1Molecular Biology Institute, University of California, Los Angeles, CA 90095
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William J. O’Shaughnessy
2Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Andy S. Moon
3Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095
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Pravin S. Dewangan
2Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Michael L. Reese
2Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390
4Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390
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  • For correspondence: pbradley@ucla.edu michael.reese@utsouthwestern.edu
Peter J. Bradley
1Molecular Biology Institute, University of California, Los Angeles, CA 90095
3Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095
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  • For correspondence: pbradley@ucla.edu michael.reese@utsouthwestern.edu
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ABSTRACT

The Toxoplasma inner membrane complex (IMC) is a specialized organelle that is crucial for the parasite to establish an intracellular lifestyle and ultimately cause disease. The IMC is composed of both membrane and cytoskeletal components, further delineated into the apical cap, body, and basal subcompartments. The apical cap cytoskeleton was recently demonstrated to govern the stability of the apical complex, which controls parasite motility, invasion, and egress. While this role was determined by individually assessing the apical cap proteins AC9, AC10, and the MAP kinase ERK7, how the three proteins collaborate to stabilize the apical complex is unknown. In this study, we use a combination of deletion analyses and yeast-2-hybrid experiments to establish that these proteins form an essential complex in the apical cap. We show that AC10 is a foundational component of the AC10:AC9:ERK7 complex and demonstrate that the interactions among them are critical to maintain the apical complex. Importantly, we identify multiple independent regions of pairwise interaction between each of the three proteins, suggesting that the AC9:AC10:ERK7 complex is organized by multivalent interactions. Together, these data support a model in which multiple interacting domains enable the oligomerization of the AC9:AC10:ERK7 complex and its assembly into the cytoskeletal IMC, which serves as a structural scaffold that concentrates ERK7 kinase activity in the apical cap.

IMPORTANCE The phylum Apicomplexa consists of obligate, intracellular parasites including the causative agents of toxoplasmosis, malaria, and cryptosporidiosis. Hallmarks of these parasites are the IMC and the apical complex, both of which are unique structures that are conserved throughout the phylum and required for parasite survival. The apical cap portion of the IMC has previously been shown to stabilize the apical complex. Here, we expand on those studies to determine the precise protein-protein interactions of the apical cap complex that confer this essential function. We describe the multivalent nature of these interactions and show that the resulting protein oligomers likely tether ERK7 in the apical cap. This study represents the first description of the architecture of the apical cap at a molecular level, expanding our understanding of the unique cell biology that drives Toxoplasma infections.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵+ P.J.B. and M.L.R. are co-principal investigators for this work.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 04, 2022.
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Multivalent interactions drive the Toxoplasma AC9:AC10:ERK7 complex to concentrate ERK7 in the apical cap
Peter S. Back, William J. O’Shaughnessy, Andy S. Moon, Pravin S. Dewangan, Michael L. Reese, Peter J. Bradley
bioRxiv 2022.01.04.474968; doi: https://doi.org/10.1101/2022.01.04.474968
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Multivalent interactions drive the Toxoplasma AC9:AC10:ERK7 complex to concentrate ERK7 in the apical cap
Peter S. Back, William J. O’Shaughnessy, Andy S. Moon, Pravin S. Dewangan, Michael L. Reese, Peter J. Bradley
bioRxiv 2022.01.04.474968; doi: https://doi.org/10.1101/2022.01.04.474968

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