Mechanisms of Membrane Targeting by C2 and PH Domains

C2 和 PH 结构域的膜靶向机制

• 批准号: 7038204
• 负责人: JOSEPH J FALKE
• 金额: $ 28.81万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038204
• 关键词: biological signal transduction; calcium ion; cell membrane; chemotaxis; chimeric proteins; electron spin resonance spectroscopy; fluorescence resonance energy transfer; fluorescence spectrometry; intracellular membranes; intracellular transport; leukocytes; lipid bilayer membrane; membrane proteins; nuclear magnetic resonance spectroscopy; phosphatidylinositol 3 kinase; phosphatidylinositols; phospholipase A2; phospholipase C; phosphomonoesterases; protein kinase C; protein signal sequence; protein structure function; protein transport; serine threonine protein kinase

DESCRIPTION (provided by applicant): This continuing project investigates the C2 and pleckstrin homology (PH) motifs, which are conserved signaling domains used as targeting modules in over 300 and 800 human proteins, respectively. Both of these motifs are activated by a second messenger then dock to a specific intracellular membrane, thereby targeting their parent proteins to the membrane surface where substrates or effectors are located. Such targeting is essential for the activation of a wide array of signaling pathways, including phosphorylation cascades, G protein circuits, calcium signaling, vesicle trafficking, phago-, endo-, and exo-cytosis, synaptic vesicle fusion and neurotransmitter release, generation of lipid-derived second messengers, control of cell growth and chemotaxis. C2 and PH domains are also linked to a wide array of human diseases ranging from cancer (C2 domain of PTEN; PH domain of protein kinase B / Akt) to inflammation (C2 domain of cytosolic phospholipase A2). Moreover, multiple C2 and PH domains are essential components of the leukocyte chemotaxis pathway responsible for tracking down invading or damaged cells marked for destruction, a pathway that is central to effective immune response. The Specific Aims of the project are to elucidate the molecular mechanisms used by C2 and PH domains to recognize and dock to their specific target membranes, to generate a structural picture of the membrane-docked states of both domains, and to develop a spatiotemporal map of the complex web of targeting events triggered by C2 and PH domains during leukocyte chemotaxis. The Progress Report describes published and preliminary results revealing the mechanisms of C2 domain calcium selectivity and activation, the mechanism of PH domain searching for its rare target lipid, and the docking geometry of membrane-bound C2 domains. Overall, the results of the proposed studies will have significant implications for a molecular understanding of C2 and PH domain signaling in human health and disease.

描述（由申请人提供）：这个持续的项目研究了C2和Pleckstrin同源（pH）基序，它们是保守的信号域，分别用作300多个和800个人类蛋白质的靶向模块。这两个基序都被第二个使者激活，然后将其扩展到特定的细胞内膜，从而将其母蛋白靶向底物或效应子所在的膜表面。这种靶向对于激活各种信号通路的激活至关重要，包括磷酸化级联，G蛋白电路，钙信号传导，囊泡运输，phago-，phago-，thago--胞菌，突触囊泡融合和神经递质的突触囊泡融合和神经释放剂释放，生成Lipid sepends derdsded derded derded derded derded septive derded seversend contereng consegex seversengex seversegs，化学疗法和化学剂。 C2和pH结构域也与各种各样的人类疾病有关，包括癌症（PTEN的C2域；蛋白激酶B / AKT的pH结构域）到炎症（胞质磷脂酶A2的C2结构域）。此外，多个C2和pH结构域是白细胞趋化途径的重要组成部分，负责跟踪标记为破坏的入侵或受损细胞，这是一种有效免疫反应的途径。该项目的具体目的是阐明C2和pH结构域使用的分子机制，以识别并将其停靠在其特定的目标膜上，以产生两个域的膜上插值状态的结构图，并开发C2和PH Domains在Leukococys of Chemaxis触发的靶向事件的复杂靶向事件的时空图。进度报告描述了已发表的和初步结果，揭示了C2结构域钙选择性和激活的机制，pH结构域寻找其稀有靶脂质的机制以及膜结合C2域的对接几何形状。总体而言，拟议研究的结果将对人类健康和疾病中C2和pH结构域信号的分子理解具有重要意义。