6EF4

Crystal structure of mouse PP2A Aalpha P179R mutant

6EF4 の概要

• エントリーDOI: 10.2210/pdb6ef4/pdb
• 分子名称: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (1 entity in total)
• 機能のキーワード: pp2a, aalpha, protein binding
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 65509.50

構造登録者

Wang, Z.,Shen, G.,Xu, W. (登録日: 2018-08-16, 公開日: 2019-06-26, 最終更新日: 2023-10-11)

主引用文献

Taylor, S.E.,O'Connor, C.M.,Wang, Z.,Shen, G.,Song, H.,Leonard, D.,Sangodkar, J.,LaVasseur, C.,Avril, S.,Waggoner, S.,Zanotti, K.,Armstrong, A.J.,Nagel, C.,Resnick, K.,Singh, S.,Jackson, M.W.,Xu, W.,Haider, S.,DiFeo, A.,Narla, G.
The Highly Recurrent PP2A A alpha-Subunit Mutation P179R Alters Protein Structure and Impairs PP2A Enzyme Function to Promote Endometrial Tumorigenesis.
Cancer Res., 79:4242-4257, 2019

PubMed Abstract: Somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene is highly prevalent in high-grade endometrial carcinoma. The structural, molecular, and biological basis by which the most recurrent endometrial carcinoma-specific mutation site P179 facilitates features of endometrial carcinoma malignancy has yet to be fully determined. Here, we used a series of structural, biochemical, and biological approaches to investigate the impact of the P179R missense mutation on PP2A function. Enhanced sampling molecular dynamics simulations showed that arginine-to-proline substitution at the P179 residue changes the protein's stable conformation profile. A crystal structure of the tumor-derived PP2A mutant revealed marked changes in A-subunit conformation. Binding to the PP2A catalytic subunit was significantly impaired, disrupting holoenzyme formation and enzymatic activity. Cancer cells were dependent on PP2A disruption for sustained tumorigenic potential, and restoration of wild-type Aα in a patient-derived P179R-mutant cell line restored enzyme function and significantly attenuated tumorigenesis and metastasis . Furthermore, small molecule-mediated therapeutic reactivation of PP2A significantly inhibited tumorigenicity . These outcomes implicate PP2A functional inactivation as a critical component of high-grade endometrial carcinoma disease pathogenesis. Moreover, they highlight PP2A reactivation as a potential therapeutic strategy for patients who harbor P179R mutations. SIGNIFICANCE: This study characterizes a highly recurrent, disease-specific PP2A mutation as a driver of endometrial carcinoma and a target for novel therapeutic development..

PubMed: 31142515
DOI: 10.1158/0008-5472.CAN-19-0218

実験手法

X-RAY DIFFRACTION (3.4 Å)