Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition

Li, Y.; Balakrishnan, V. K.; Rowse, M.; Wu, C.-G.; Bravos, A. P.; Yadav, V. K.; Ivarsson, Y.; Strack, S.; Novikova, I. V.; Xing, Y.

doi:10.1101/2022.07.01.498399

bioRxiv · 10.1101/2022.07.01.498399

Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition

Li, Y.·Balakrishnan, V. K.·Rowse, M.·Wu, C.-G.·Bravos, A. P.·Yadav, V. K.·Ivarsson, Y.·Strack, S.·Novikova, I. V.·Xing, Y.

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Abstract

Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro. The high-resolution cryo-EM structure of a PP2A-B56 holoenzyme-PME-1 complex reveals that PME-1 disordered regions, including a substrate-mimicking motif, tether to the B56 regulatory subunit at remote sites. They occupy the holoenzyme substrate-binding groove and allow large structural shifts in both holoenzyme and PME-1 to enable multi-partite contacts at structured cores to activate the methylesterase. B56-interface mutations selectively block PME-1 activity toward PP2A-B56 holoenzymes and affect the methylation of a fraction of total cellular PP2A. The B56-interface mutations allow us to uncover B56-specific PME-1 functions in p53 signaling. Our studies reveal multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile PME-1 activities derived from coupling substrate-mimicking motifs to dynamic structured cores.

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Li, Y., Balakrishnan, V. K., Rowse, M., Wu, C.-G., Bravos, A. P., Yadav, V. K., Ivarsson, Y., Strack, S., Novikova, I. V., Xing, Y.. 2022-07-01. Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition. https://doi.org/10.1101/2022.07.01.498399

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