Theoretical study of structure-function correlations of Aquaporin V and mutants

水通道蛋白V及其突变体结构-功能相关性的理论研究

• 批准号: 8414118
• 负责人: LIAO Y CHEN
• 金额: $ 11.03万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414118
• 关键词: AQP1 gene; Affinity; Antineoplastic Agents; Apoptosis; Binding; Biological Models; Biological Process; Body of pancreas; Cell Proliferation; Cell membrane; Cells; Chemicals; Colon; Computer Simulation; Disease; Drug Design; Duodenum; Environment; Event; Eye; Free Energy; Gases; Goals; High Performance Computing; Histidine; Human; Human body; In Vitro; Ions; Knowledge; Labyrinth; Lacrimal gland structure; Lead; Light; Lipid Binding; Lipids; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Medicine; Methods; Modification; Molecular Conformation; Mutation; Pancreas; Permeability; Pharmaceutical Preparations; Phosphorylation; Physiological; Play; Proteins; Protomer; Research; Resolution; Role; Saline; Salivary Glands; Sampling; Signal Transduction; Site; Sjogren' s Syndrome; Solvents; Specificity; Stomach; Structure; Sweat Glands; System; Testing; Theoretical Studies; Time; Water; Woman; base; biological systems; computing resources; design; environmental change; innovation; mutant; overexpression; prevent; protein structure; protonation; public health relevance; research study; response; trafficking; water channel

DESCRIPTION (provided by applicant): Among the thirteen human aquaporins (AQP0-AQP12) distributed within cells of the stomach, duodenum, pancreas, airways, lungs, salivary glands, sweat glands, eyes, lacrimal glands, and the inner ear, AQP5 has been implicated in Sjogren's disease and in cancers of the lung, pancreas, colon etc.. Defective trafficking of AQP5 was found responsible for Sjogren's disease which inflicts about 4 million people (mostly women) in the US. Overexpression of AQP5 was identified in promoting cell proliferation and inhibiting apoptosis. Meanwhile, high-resolution x-ray structure of AQP5 has recently been determined. AQP5 resembles other aquaporins in its tetrameric conformation and in its water pore structure formed by each protomer. However, it lacks the four-fold quasi-symmetry among its four protomers and it contains a lipid, PS6, in its central pore. In light of the existent in vtro studies of AQP5's functions and its crystal structure, the following questions stand out: How does the structure of AQP5 embedded in the cell membrane under physiological conditions deviate from its crystallographic form? Does PS6 gate or inhibit the central pore? What are the specificities of the lipid-AQP5 interaction? How does the protein respond to its environmental changes in pH? And how does it respond to chemical modifications to its residues? These questions on the structure-function correlations of AQP5 need to be answered before new drugs can be designed that specifically target this protein. Answering these questions requires conducting extensive in silico experiments in an innovated approach. Two all-atom model systems of AQP5 embedded in a patch of lipid bi- layer explicitly solvated in physiological saline will be investigated: One with PS6 in the central pore of AQP5 and one without. Three specific aims will be pursued: 1.Determine the roles of the lipid in the central pore and identify the mechanism of its gating or inhibiting action. 2. Identify the protein's mechanisms of biological functions and determine its response to environmental changes. 3. Quantify AQP5's response to chemical modifications and thus identify the mechanisms of signaling, gating, or inhibiting its physiological functions. Upon completion of the proposed research, a detailed understanding will be achieved about AQP5's structure- function correlations: AQP5's degree of accessibility for trafficking before and after phosphorylation at the selected sites, the affinity and specificit of binding a lipid in its central pore, and the mechanisms of inhibiting and gating its physiological functions. The knowledge so gained will positively impact on finding new medicines to prevent and control AQP5-related diseases.

描述（申请人提供）：分布在胃、十二指肠、胰腺、气道、肺、唾液腺、汗腺、眼睛、泪腺和内耳细胞内的 13 种人类水通道蛋白（AQP0-AQP12）中，AQP5 具有与干燥病以及肺癌、胰腺癌、结肠癌等有关。有缺陷的贩运AQP5被发现与干燥病有关，该病在美国影响了约400万人（主要是女性）。 AQP5 的过度表达可促进细胞增殖并抑制细胞凋亡。 同时，AQP5的高分辨率X射线结构最近已被确定。 AQP5 的四聚体构象和每个原聚体形成的水孔结构与其他水通道蛋白相似。然而，它的四个原聚体之间缺乏四重准对称性，并且在其中心孔中含有脂质 PS6。鉴于现有的AQP5功能及其晶体结构的体外研究，以下问题很突出：生理条件下嵌入细胞膜的AQP5结构如何偏离其晶体形态？ PS6 是否会关闭或抑制中央孔？脂质-AQP5 相互作用的特殊性是什么？蛋白质如何响应环境 pH 值的变化？它对其残基的化学修饰有何反应？在设计专门针对该蛋白的新药物之前，需要回答有关 AQP5 结构与功能相关性的这些问题。回答这些问题需要以创新的方法进行广泛的计算机实验。将研究嵌入在生理盐水中明确溶剂化的脂质双层斑块中的 AQP5 的两个全原子模型系统：一个在 AQP5 的中心孔中含有 PS6，另一个则没有。我们将追求三个具体目标： 1.确定脂质在中心孔中的作用并确定其门控或抑制作用的机制。 2. 识别蛋白质的生物学功能机制并确定其对环境变化的反应。 3. 量化 AQP5 对化学修饰的反应，从而确定信号传导、门控或抑制其生理功能的机制。完成拟议的研究后，将详细了解 AQP5 的结构-功能相关性：AQP5 在选定位点磷酸化之前和之后运输的可及性程度，在其中心孔中结合脂质的亲和力和特异性，以及抑制和门控其生理功能的机制。由此获得的知识将对寻找预防和控制 AQP5 相关疾病的新药物产生积极影响。