# Structural and Cellular Choreography for Decommissioning and Recycling of PP2A Holoenzymes

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $318,718

## Abstract

PROJECT SUMMARY
Protein phosphatase 2A (PP2A) is a ubiquitous and the most prominant Ser/Thr phosphatase that regulates the
phosphorylation status of a large number of cellular proteins involved in diverse biological pathways.
Derulagulation of PP2A is associated with many human cancers, Alzheimer's Disease and susceptibility to
pathogens. The PP2A core enzyme is a heterodimer of highly conserved scaffold and catalytic subunits, which
forms the heterotrimeric holoenzyme by binding a variable and highly diverse regulatory subunit that determines
substrate selectivity. Built on recent advance on structural choreography of tight control of PP2A holoenzyme
biogenesis, in particular, the conformational switches of PP2Ac required for its latency and activation, we further
made a striking observation on recycling of PP2Ac from holoenzymes. We also observed a novel function of
PME-1 (PP2A-specific methylesterase 1) in demethylation of and interaction with PP2A holoenzymes; PME-1
was previously thought to specifically act on the core enzyme. The research proposed here will extend our
preliminary electron microscopic analyses of PP2A complexes, and use structural, biochemical, biophysical and
cell biological approaches to elucidate mechanisms that control novel function and mechanism of PME-1 in
holoenzyme regulation (Specific Aim 1), recycling of PP2Ac from PP2A holoenzymes (Specific Aim 2), and novel
insights into PP2A holoenzyme biogenesis and recycling and the multi-faceted roles of PME-1 in cellular
signaling. These studies will establish a novel regulation loop of PP2A holoenzyme biogenesis and recycling for
precise and dynamic control of PP2A holoenzymes in diverse cellular and physiological processes, and provides
a novel framework for understanding the mechanisms that regulate PP2A functions in normal and transformed
human cells.

## Key facts

- **NIH application ID:** 10372153
- **Project number:** 5R01GM137090-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Yongna Xing
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $318,718
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372153

## Citation

> US National Institutes of Health, RePORTER application 10372153, Structural and Cellular Choreography for Decommissioning and Recycling of PP2A Holoenzymes (5R01GM137090-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10372153. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*