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Protein Phosphatase 1 Holoenzyme Formation

蛋白磷酸酶 1 全酶形成

基本信息

批准号：
10441693
负责人：
Wolfgang Peti
金额：
$ 40.03万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441693
关键词：
ATP phosphohydrolase Area Binding Binding Proteins Biochemical Biogenesis Biological Biological Process Biology Biophysics Cells Cellular biology Complex Cysteine Data Development Disease Dissociation Drug Targeting Enzymes Essential Genes Eukaryota Eukaryotic Cell Excision Genetic Goals Health Holoenzymes Hydrolysis Individual Laboratories Location Malignant Neoplasms Metals Mitosis Molecular Molecular Chaperones Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Protein Dephosphorylation Protein phosphatase Proteins Reaction Regulation Research Research Personnel Research Project Grants Role Serine/Threonine Phosphorylation Signal Transduction Structure Substrate Specificity Testing Threonine Phosphorylation Site Work Yeasts biophysical tools cell growth dimer experimental study human disease inhibitor inorganic phosphate insight novel novel strategies protein phosphatase inhibitor-1 response structural biology tool ubiquitin-protein ligase yeast genetics

项目摘要

ABSTRACT Phosphorylation is one of the most ubiquitous, reversible posttranslational modifications in cells. The enzymes responsible for controlling the phosphorylation state of the cell are kinases, which catalyze the transfer of the γ-phosphate moiety of ATP to substrates, and phosphatases, which catalyze the reverse hydrolysis reaction, the removal of the phosphate moiety from phosphorylated substrates. Thus, phosphatases dynamically reverse the effects of kinases. Because phosphorylation is critical for all biological processes from cell growth to differentiation to development, the location and duration of the reciprocal actions of kinases and phosphatases must be exquisitely regulated both temporally and spatially within the cell. Consequently, when this tight regulation is disrupted, dysregulation of phosphorylation signaling ensues and the consequence is most often disease. Deletion of either one of two PP1 regulators—SDS22 (PPP1R7) or Inhibitor-3 (I3; PPP1R11 or Ypi1 in yeast)—is lethal in yeast (essential genes), highlighting their biological significance. However, since their discovery, different biological roles have been assigned to SDS22 and I3, including roles in mitosis (SDS22), E3 ligase functionality (I3), PP1 biogenesis, among others. Thus, while it is clear that SDS22 and I3 are essential PP1 regulators, their true biological function(s) and especially their mechanism(s) of action are still unknown. This has hindered progress in understanding their roles in PP1 biology. In cells, these proteins form both heterodimeric (SDS22:PP1 and I3:PP1) and a heterotrimeric (SDS22:I3:PP1; SIP) PP1 complex. The structure and function(s) of the individual dimeric complexes, if and how the structure and function(s) of the trimeric complex differs from those of the dimeric complexes and the role(s) of each complex in PP1 holoenzyme formation are major questions in the field. Further, additional data suggest that dissociation of the SIP complex requires the AAA+ ATPase p37/p97. However, the molecular details of SIP complex dissociation have also remained elusive. The presented research project uses a powerful integrated approach that combines structural biology with biochemical and cell biology experiments to obtain novel insights into the molecular mechanisms used by these regulators to control PP1 activity and direct PP1 holoenzyme assembly. Because PP1 holoenzymes have critical roles in human diseases, the proposed work will provide novel strategies for selectively inhibiting PP1 activity by targeting the PP1 holoenzyme formation and subunit exchange, which is essential for understanding how distinct PPPs contribute to disease.

摘要