期刊
ELIFE
卷 11, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.79736
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资金
- National Institute of General Medical Sciences [GM137090-01, GM096060-01]
- American Cancer Society [RSG-10-153-01-DMC]
- Jordan's Guardian Angels Foundation and Jordan's Syndrome research consortium fund from the State of California [A19-3376-5007]
This study demonstrates that PME-1 can regulate different families of PP2A holoenzymes and block substrate recognition. The high-resolution cryoelectron microscopy structure reveals the binding mode of PME-1 with the B56 regulatory subunit and the selective impact on PP2A-B56 holoenzymes. The findings uncover multiple mechanisms of PME-1 in suppressing holoenzyme functions and versatile activities.
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 substratebinding 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.
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