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

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 cryoelectron microscopy 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 multipartite 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.

• Authors: Yitong Li, Vijaya Kumar Balakrishnan, Michael Rowse, Cheng-Guo Wu, Anastasia Phoebe Bravos, Vikash K Yadav, Ylva Ivarsson, Stefan Strack, Irina V Novikova, Yongna Xing
• Journal: eLife (Elife) Vol. 11 (08 04 2022) ISSN: 2050-084X [Electronic] England
• PMID: 35924897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Holoenzymes
• Protein Phosphatase 2

Topics

• Cryoelectron Microscopy
• Demethylation
• Holoenzymes (metabolism)
• Methylation
• Protein Phosphatase 2 (metabolism)