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Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis

View ORCID ProfilePeter S. Back, William J. O’Shaughnessy, Andy S. Moon, Pravin S. Dewangan, Xiaoyu Hu, Jihui Sha, James A. Wohlschlegel, View ORCID ProfilePeter J. Bradley, View ORCID ProfileMichael L. Reese
doi: https://doi.org/10.1101/2020.02.02.931089
Peter S. Back
1Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California
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William J. O’Shaughnessy
2Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
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Andy S. Moon
3Department of Molecular Microbiology and Immunology, University of California, Los Angeles, CA USA
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Pravin S. Dewangan
2Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
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Xiaoyu Hu
2Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
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Jihui Sha
4Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
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James A. Wohlschlegel
4Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
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Peter J. Bradley
1Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California
3Department of Molecular Microbiology and Immunology, University of California, Los Angeles, CA USA
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  • For correspondence: michael.reese@utsouthwestern.edu pbradley@ucla.edu
Michael L. Reese
2Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
5Department of Biochemistry, University of Texas, Southwestern Medical Center, Dallas, TX USA
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  • For correspondence: michael.reese@utsouthwestern.edu pbradley@ucla.edu
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Abstract

Apicomplexan parasites use a specialized cilium structure called the apical complex to organize their secretory organelles and invasion machinery. The apical complex is integrally associated with both the parasite plasma membrane and an intermediate filament cytoskeleton called the inner membrane complex (IMC). While the apical complex is essential to the parasitic lifestyle, little is known about the regulation of apical complex biogenesis. Here, we identify AC9 (apical cap protein 9), a largely intrinsically disordered component of the Toxoplasma gondii IMC, as essential for apical complex development, and therefore for host cell invasion and egress. Parasites lacking AC9 fail to successfully assemble the tubulin-rich core of their apical complex, called the conoid. We use proximity biotinylation to identify the AC9 interaction network, which includes the kinase ERK7. Like AC9, ERK7 is required for apical complex biogenesis. We demonstrate that AC9 directly binds ERK7 through a conserved C-terminal motif and that this interaction is essential for ERK7 localization and function at the apical cap. The crystal structure of the ERK7:AC9 complex reveals that AC9 is not only a scaffold, but also inhibits ERK7 through an unusual set of contacts that displaces nucleotide from the kinase active site. ERK7 is an ancient and auto-activating member of the mitogen-activated kinase family and we have identified its first regulator in any organism. We propose that AC9 dually regulates ERK7 by scaffolding and concentrating it at its site of action while maintaining it in an “off” state until the specific binding of a true substrate.

Significance Statement Apicomplexan parasites include the organisms that cause widespread and devastating human diseases such as malaria, cryptosporidiosis, and toxoplasmosis. These parasites are named for a structure, called the “apical complex,” that organizes their invasion and secretory machinery. We found that two proteins, apical cap protein 9 (AC9) and an enzyme called ERK7 work together to facilitate apical complex assembly. Intriguingly, ERK7 is an ancient molecule that is found throughout Eukaryota, though its regulation and function are poorly understood. AC9 is a scaffold that concentrates ERK7 at the base of the developing apical complex. In addition, AC9 binding likely confers substrate selectivity upon ERK7. This simple competitive regulatory model may be a powerful but largely overlooked mechanism throughout biology.

Footnotes

  • Additional biochemical data added (Figures 5, 6, S3)

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted March 20, 2020.
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Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis
Peter S. Back, William J. O’Shaughnessy, Andy S. Moon, Pravin S. Dewangan, Xiaoyu Hu, Jihui Sha, James A. Wohlschlegel, Peter J. Bradley, Michael L. Reese
bioRxiv 2020.02.02.931089; doi: https://doi.org/10.1101/2020.02.02.931089
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Ancient MAPK ERK7 is regulated by an unusual inhibitory scaffold required for Toxoplasma apical complex biogenesis
Peter S. Back, William J. O’Shaughnessy, Andy S. Moon, Pravin S. Dewangan, Xiaoyu Hu, Jihui Sha, James A. Wohlschlegel, Peter J. Bradley, Michael L. Reese
bioRxiv 2020.02.02.931089; doi: https://doi.org/10.1101/2020.02.02.931089

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