# Structural basis of PP2A phosphatase diseases

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $361,963

## Abstract

PROJECT SUMMARY
Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase with complex regulation and composition.
Deregulation of PP2A holoenzymes leads to devastating human diseases, including multiple types of cancer and
neurological disorders. In recent years, whole exome/genome sequencing for the molecular diagnosis identified
broad disease mutations in PP2A subunits and substrates in cancer and neurological disorders. The diagnosis
of de novo PP2A mutations in developmental disorders enthused unprecedented multidisciplinary phosphatase
research and interactions with patient families. De novo mutations in several members of B56 family of PP2A
regulatory subunits, such as B56δ and B56γ, cause neurological disorders, known as Jordan Syndrome. The
same somatic mutations were found in cancer patients. Built on our preliminary cryo-EM, molecular dynamic
simulations, biochemical, single molecule, reverse phase protein array, and cell biology studies, here we aim to
decipher the mechanisms of B56 disease mutations in cancer and intellectual disabilities. We will determine the
cryo-EM structures of WT and disease variants of the PP2A-B56δ holoenzyme (Specific Aim 1), investigate how
intellectual disability (ID) mutations alter holoenzyme dynamics, activation phosphorylation, and interactions with
regulatory proteins, combining biochemical dissections, advanced molecular dynamic simulation approaches,
and single-molecule fluorescence resonance energy transfer (smFRET) (Specific Aim 2), and test our hypothesis
on the discriminating and merging mechanisms of B56δ and B56γ ID mutations in perturbing the cAMP negative
feedback signaling via MAPK and CREB signaling, respectively (Specific Aim 3). These studies will shed light
on a highly dynamic regulation machinery involving the folding of long disordered regions against the
holoenzyme core and a super-long dynamic interface harboring the majority of residues mutated in Jordan
Syndrome, multiple activation phophorylation sites, and regulatory elements that suppress both the phosphatase
active site and the substrate-binding groove.

## Key facts

- **NIH application ID:** 10907816
- **Project number:** 5R01GM145811-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Yongna Xing
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $361,963
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907816

## Citation

> US National Institutes of Health, RePORTER application 10907816, Structural basis of PP2A phosphatase diseases (5R01GM145811-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10907816. Licensed CC0.

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