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Structural and Cellular Choreography for Decommissioning and Recycling of PP2A Holoenzymes

PP2A 全酶退役和回收的结构和细胞编排

基本信息

批准号：
10210932
负责人：
Yongna Xing
金额：
$ 31.85万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10210932
关键词：
Active Sites Address Affinity Alzheimer&apos s Disease Back Binding Binding Sites Biochemical Biogenesis Biological Biophysics Catalytic Domain Cell Cycle Cell Death Cell physiology Cells Complex Cryoelectron Microscopy DNA Damage Data Disease Disease susceptibility Dissociation Electrons Enzymes Family Heart Diseases Holoenzymes Human Ions Knowledge Malignant Neoplasms Mammalian Cell Mediating Metals Methylation Microscopic Molecular Molecular Chaperones Molecular Conformation Mutation Names Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Physiological Processes Process Protein Analysis Protein Deregulation Protein phosphatase Proteins Publishing Recycling Regulation Research Resolution Role Series Signal Pathway Signal Transduction Structure Viral Pathogenesis base cancer type chelation demethylation human disease insight interdisciplinary approach metalloenzyme nanomolar nervous system disorder novel particle pathogen protein folding response scaffold

项目摘要

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.

项目总结