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：
10372153
负责人：
Yongna Xing
金额：
$ 31.87万
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/10372153
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.

项目摘要蛋白质磷酸酶2a（PP2A）是一种无处不在，最突出的SER/THR磷酸酶，可调节许多参与多种生物途径的细胞蛋白的磷酸化状态。 PP2A的衍射与许多人类癌症，阿尔茨海默氏病以及对病原体。 PP2A核心酶是高度保守的支架和催化亚基的异二聚体，通过结合一个确定的可变且高度多样的调节亚基来形成异三聚体全酶底物选择性。建立在最新的PP2A全酶紧密控制结构编排的基础上特别是生物发生，PP2AC的延迟和激活所需的PP2AC的构象转换，我们进一步对全酶的PP2AC回收进行了惊人的观察。我们还观察到了一个新颖的功能 PME-1（PP2A特异性甲基酯酶1）在与PP2A全酶相互作用的脱甲基化和相互作用中； PME-1 以前被认为是针对核心酶的。这里提出的研究将扩大我们的 PP2A复合物的初步电子显微镜分析，并使用结构，生化，生物物理和细胞生物学方法阐明控制PME-1的新功能和机制的机制全酶调节（特定目标1），PP2A全酶的PP2AC回收（特定AIM 2）和新颖对PP2A全酶生物发生和回收利用以及PME-1在细胞中的多面作用的见解信号。这些研究将建立一个新的PP2A全酶生物发生和回收的调节环。 PP2A全酶在多种细胞和生理过程中的精确和动态控制，并提供一个新的框架，用于理解调节pp2a在正常和转化中起作用的机制人类细胞。