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Divergent kinase WNG1 is regulated by phosphorylation of an atypical activation sub-domain

View ORCID ProfilePravin S. Dewangan, Tsebaot Beraki, View ORCID ProfileElisia A. Paiz, Delia A. Mensah, View ORCID ProfileZhe Chen, View ORCID ProfileMichael L. Reese
doi: https://doi.org/10.1101/2022.03.02.482640
Pravin S. Dewangan
1Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
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Tsebaot Beraki
1Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
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Elisia A. Paiz
1Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
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Delia A. Mensah
1Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
2Honors College, University of Texas at Dallas, Richardson, TX USA
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Zhe Chen
3Department of Biophysics, University of Texas, Southwestern Medical Center, Dallas, TX USA
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Michael L. Reese
1Department of Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX USA
4Department of Biochemistry, University of Texas, Southwestern Medical Center, Dallas, TX USA
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  • For correspondence: michael.reese@utsouthwestern.edu
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Abstract

Apicomplexan parasites like Toxoplasma gondii grow and replicate within a specialized organelle called the parasitophorous vacuole. The vacuole is decorated with parasite proteins that integrate into the membrane after trafficking through the parasite secretory system as soluble, chaperoned complexes. A regulator of this process is an atypical protein kinase called WNG1. Phosphorylation by WNG1 appears to serve as a switch for membrane integration. However, like its substrates, WNG1 is secreted from the parasite dense granules, and its activity must therefore be tightly regulated until the correct membrane is encountered. Here we demonstrate that, while another member of the WNG family can adopt multiple multimeric states, WNG1 is monomeric and therefore not regulated by multimerization. Instead, we identify two phosphosites on WNG1 that are required for its kinase activity. Using a combination of in vitro biochemistry and structural modeling, we identify basic residues that are also required for WNG1 activity and therefore appear to recognize the activating phosphosites. Among these coordinating residues are the “HRD” Arg, which recognizes activation loop phosphorylation in canonical kinases. WNG1, however, is not phosphorylated on its activation loop, and its activating phosphosites instead appear to lock the kinase C-lobe into an activated conformation. These data suggest a simple model for WNG1 activation by increasing ATP concentration above a critical threshold once WNG1 traffics to the parasitophorous vacuole.

Competing Interest Statement

The authors have declared no competing interest.

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 4.0 International license.
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Posted March 02, 2022.
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Divergent kinase WNG1 is regulated by phosphorylation of an atypical activation sub-domain
Pravin S. Dewangan, Tsebaot Beraki, Elisia A. Paiz, Delia A. Mensah, Zhe Chen, Michael L. Reese
bioRxiv 2022.03.02.482640; doi: https://doi.org/10.1101/2022.03.02.482640
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Divergent kinase WNG1 is regulated by phosphorylation of an atypical activation sub-domain
Pravin S. Dewangan, Tsebaot Beraki, Elisia A. Paiz, Delia A. Mensah, Zhe Chen, Michael L. Reese
bioRxiv 2022.03.02.482640; doi: https://doi.org/10.1101/2022.03.02.482640

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