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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, James L Wohlschlegel, Jihui Sha, View ORCID ProfilePeter Bradley, View ORCID ProfileMichael L Reese
doi: https://doi.org/10.1101/2020.02.02.931089
Peter S Back
University of California, Los Angeles;
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  • For correspondence: peterback@g.ucla.edu
William J O'Shaughnessy
UT Southwestern Medical Center
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  • For correspondence: william.oshaughnessy@utsouthwestern.edu
Andy S Moon
University of California, Los Angeles;
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  • For correspondence: moonsh@ucla.edu
Pravin S Dewangan
UT Southwestern Medical Center
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  • For correspondence: pravin.dewangan@utsouthwestern.edu
James L Wohlschlegel
University of California, Los Angeles;
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  • For correspondence: jwohl@ucla.edu
Jihui Sha
University of California, Los Angeles;
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  • For correspondence: jihuisha@hotmail.com
Peter Bradley
University of California, Los Angeles;
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  • For correspondence: pbradley@ucla.edu
Michael L Reese
UT Southwestern Medical Center
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  • For correspondence: michael.reese@utsouthwestern.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), an 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.

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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 4.0 International license.
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Posted February 02, 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, James L Wohlschlegel, Jihui Sha, Peter 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, James L Wohlschlegel, Jihui Sha, Peter Bradley, Michael L Reese
bioRxiv 2020.02.02.931089; doi: https://doi.org/10.1101/2020.02.02.931089

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