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Article
Yongna Xing
University of Wisconsin-Madison
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9834-528X
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This work is licensed under a CC BY 4.0 License. Read Full License
Protein phosphatase 2A (PP2A) methylesterase 1 (PME-1) is cancer-promoting but essential for development, and long-believed to remove carboxymethylation, a central modification, from the common PP2A core enzyme but not diverse holoenzymes that target broad cellular signaling by recognizing specific disordered motifs via regulatory subunits. On the contrary, our biochemical dissection and high-resolution cryo-EM structural analysis of a PP2A-B’ holoenzyme-PME-1 complex reveal that PME-1 disordered motifs, including phosphatase substrate-mimicking motifs, tether to the holoenzyme at remote sites, block its substrate binding, and allow large structural shifts in both holoenzyme and PME-1 to enable multiptle dynamic structured contacts and induce methylesterase activation toward the holoenzyme. PME-1 inhibitor and B’-interface mutations differentially modulate cellular PP2A methylation and allow us to uncover cellular PME-1 functions in AKT-p53 signaling. Our studies demonstrate how dynamic structured cores and disordered motifs create versatile activities and lay a foundation for investigating and targeting multifaceted activities toward broad PP2A complexes in cellular signaling.
Keywords
Biochemical Dissections, Disordered Motifs, Multiple Dynamic Structured Contacts, Methylesterase Activation, AKT-p53 Signaling
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There is NO Competing Interest.
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Yongna Xing
University of Wisconsin-Madison
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9834-528X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 03 May, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Protein phosphatase 2A (PP2A) methylesterase 1 (PME-1) is cancer-promoting but essential for development, and long-believed to remove carboxymethylation, a central modification, from the common PP2A core enzyme but not diverse holoenzymes that target broad cellular signaling by recognizing specific disordered motifs via regulatory subunits. On the contrary, our biochemical dissection and high-resolution cryo-EM structural analysis of a PP2A-B’ holoenzyme-PME-1 complex reveal that PME-1 disordered motifs, including phosphatase substrate-mimicking motifs, tether to the holoenzyme at remote sites, block its substrate binding, and allow large structural shifts in both holoenzyme and PME-1 to enable multiptle dynamic structured contacts and induce methylesterase activation toward the holoenzyme. PME-1 inhibitor and B’-interface mutations differentially modulate cellular PP2A methylation and allow us to uncover cellular PME-1 functions in AKT-p53 signaling. Our studies demonstrate how dynamic structured cores and disordered motifs create versatile activities and lay a foundation for investigating and targeting multifaceted activities toward broad PP2A complexes in cellular signaling.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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