Structural and functional studies of protein kinase C regulation

蛋白激酶C调节的结构和功能研究

• 批准号: 10379378
• 负责人: Tatyana I. Igumenova
• 金额: $ 30.61万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379378
• 关键词: AIDS/HIV problem; Address; Affinity; Alzheimer' s Disease; Basic Science; Binding; Binding Sites; Biochemical; Biophysics; Cells; Chemicals; Complex; Coupled; Data; Detection; Development; Diabetes Mellitus; Diglycerides; Ensure; Enzymes; Eukaryotic Cell; Event; Exhibits; Family; Funding; Health; Heart Diseases; Human; Human Pathology; Hydrophobicity; In Vitro; Isoenzymes; Knowledge; Ligands; Lipids; Malignant Neoplasms; Membrane; Membrane Lipids; Membrane Proteins; Molecular; Molecular Conformation; Mutation; Outcome; Pharmacologic Substance; Pharmacology; Phenotype; Phosphatidylinositols; Phospholipids; Phosphotransferases; Play; Process; Protein Kinase C; Protein Kinase C Inhibitor; Proteins; Regulation; Research Proposals; Resolution; Role; Signal Pathway; Signal Transduction; Signaling Protein; Structural Models; Structure; System; Tertiary Protein Structure; Testing; Therapeutic Human Experimentation; Tumor Promoters; Tumor Suppressor Proteins; biophysical techniques; design; experimental study; falls; insight; molecular dynamics; novel; phosphatidylinositol phosphate, PtdIns(4,5)P2; prevent; protein activation; protein kinase modulator; recruit; response; simulation; tumor progression; two-dimensional

Protein Kinases C (PKC) define a family of lipid-activated kinases that are key effectors of phosphoinositide signaling – a major intracellular signaling pathway of eukaryotic cells. Consistent with this central activity, dysregulation of PKC signaling is implicated in cancer progression, cardiac disease, diabetes, and Alzheimer's disease. Because of the fundamental role of PKC in signal transduction, the development of modulators of PKC activity – both for therapeutic and basic research purposes – is widely recognized as one of the major challenges in the field. Addressing these challenges requires an atomic-level understanding of PKC control – in particular, how lipids regulate PKC activity. This subject defines a major gap in understanding of PKC regulatory mechanisms. The central objective of this research proposal is to decipher the mechanism of the key event that triggers activation of PKC – its interaction with diacylglycerol (DAG). It is currently unknown how DAG is recognized and captured in membranes by the conserved homology 1 (C1) domains of PKC. To address this critical gap in knowledge, a synergistic combination of advanced solution NMR approaches, atomistic molecular dynamics simulations, and biochemical strategies will be applied to address the following Specific Aims: (1) to understand the molecular basis of diacylglycerol recognition by C1 domains, (2) to decipher precisely how C1 domains are initially recruited to membranes, and (3) to determine how tandem C1 domains execute a coincidence detection of DAG and anionic phospholipids. Insights into the DAG-sensing mechanism obtained from the proposed studies will have impact that extends beyond the already large problem of PKC regulation. The atomic-level information regarding C1-DAG interactions will be directly applicable to five other large families of signaling proteins that rely on C1 domains for regulation of their DAG- dependent activities. This information will also facilitate the design of pharmacological agents for rational modulation of PKC function by direct targeting of its C1 domains.

蛋白激酶C （PKC）定义了一个脂质活化激酶家族，是磷酸肌肽的关键效应物