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（由申请人提供）：在分布于胃、十二指肠、胰腺、气道、肺、唾液腺、汗腺、眼、泪腺和内耳的细胞内的13种人水通道蛋白（AQP 0-AQP 12）中，AQP 5与舍格伦病以及肺癌、胰腺癌、结肠癌等有关。AQP 5的缺陷贩运被发现对干燥病负责，该疾病在美国造成约400万人（主要是妇女）。过表达AQP 5可促进细胞增殖，抑制细胞凋亡。 与此同时，最近已经确定了AQP 5的高分辨率X射线结构。AQP 5在其四聚体构象和由每个原聚体形成的水孔结构方面与其他水通道蛋白相似。然而，它缺乏四重准对称性之间的四个原聚体，它包含一个脂质，PS 6，在其中央孔。鉴于目前对AQP 5的功能和晶体结构的体外研究，以下问题突出：在生理条件下，嵌入细胞膜的AQP 5的结构如何偏离其晶体学形式？PS 6是否会门控或抑制中心孔？脂质-AQP 5相互作用的特异性是什么？蛋白质如何响应pH值的环境变化？它对残留物的化学修饰有何反应？这些关于AQP 5的结构-功能相关性的问题需要在设计专门针对这种蛋白质的新药之前得到回答。解决这些问题需要以创新的方法进行广泛的计算机实验。将研究嵌入在明确溶剂化于生理盐水中的脂质双层片中的AQP 5的两个全原子模型系统：一个在AQP 5的中心孔中具有PS 6，另一个没有PS 6。本研究的目的有三：1.确定脂质在中央孔中的作用，并确定其门控或抑制作用的机制。2.确定蛋白质的生物功能机制，并确定其对环境变化的反应。3.量化AQP 5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。本研究完成后，将对AQP 5的结构与功能的关系有一个详细的了解：AQP 5在磷酸化前后的运输可及性程度，在其中心孔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发现预防和控制AQP 5相关疾病的新药产生积极影响。