STRUCTURE OF THE NUCLEOTIDE-BINDING DOMAINS OF HUMAN COPPER-TRANSPORTING ATPASES

人铜转运ATP酶的核苷酸结合域的结构

• 批准号: 7721645
• 负责人: OLEG Y DMITRIEV
• 金额: $ 0.18万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721645
• 关键词: ATP phosphohydrolase; Binding; Binding Sites; Biochemical; Ca(2+)-Transporting ATPase; Class; Computer Retrieval of Information on Scientific Projects Database; Copper; Data Collection; Disease; Environment; Enzymes; Funding; Future; Genes; Goals; Grant; Heavy Metals; Hepatolenticular Degeneration; Human; Inborn Errors of Metabolism; Institution; Location; Menkes Kinky Hair Syndrome; Metabolism; Mutation; N Domain; Nucleotides; Process; Property; Proteins; Publishing; Regulation; Research; Research Personnel; Resolution; Resources; Solutions; Source; Structure; Surface; Transmembrane Transport; United States National Institutes of Health; Variant; Walkers; Wilson disease protein; copper-transporting ATPase; disease-causing mutation; domain mapping; human tissue; mutant; three dimensional structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this project is to solve the structures of the nucleotide binding domains of the two human copper-transporting ATPases, Wilson disease associated protein and Menkes disease associated protein and to elucidate conformational changes caused in the domains by ATP binding. The copper-transporting ATPases belong to a distinct and poorly studied class of membrane transport enzymes (Lutsenko et al., 2002) and are essential for copper-metabolism in human tissues. Mutations in the ATP7A and ATP7B genes encoding these proteins result in severe hereditary metabolic disorders. No high-resolution structure of a heavy metal transporting ATPase has been published to date.The structures of the nucleotide binding domains will be solved in the nucleotide-free and ATP-bound forms. Location of the ATP -binding site in the three-dimensional structure of the domains will be determined. Conformational changes taking place upon ATP binding will be studied in the context of the catalytic cycle of the P-type ATPases, with the emphasis on unique features separating heavy-metal transporting ATPases from well studied Ca2+-ATPase. The differences in the three-dimensional structures of the nucleotide binding domains of Wilson disease and Menkes disease proteins associated with non-homologous regions of primary structure will be determined. This project will also provide groundwork for the future studies of the structural effects of disease-causing mutations in the copper-transporting ATPases, for solving the structures of the larger domains of Wilson and Menkes disease proteins and mapping the domain-domain interaction surfaces. To date the structure of the N-nucleotide-binding domain of the Wilson disease ATPase (WNABD) comprising residues 1036-1196 has been solved in ATP bound form (Dmitriev et al., 2006). Data collection and processing for structure determination of two disease-causing mutant variants of the N-domain (E1064A and H1069A) is in progressReferences 1. Dmitriev, O., Tsivkovskii, R., Abildgaard, F., Morgan, C. T., Markley, J. L., and Lutsenko, S. (2006) Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations Proc. Natl. Acad. Sci. U. S. A 103, 5302-5307. 2. Lutsenko, S., Efremov, R. G., Tsivkovskii, R., and Walker, J. M. (2002) Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation J. Bioenerg. Biomembr. 34, 351-362.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目的目的是解决两个人类铜转运ATPases的核苷酸结合结构域的结构，Wilson疾病相关的蛋白质和Menkes疾病相关的蛋白质，并阐明ATP结合引起的域引起的构象变化。铜运输ATPases属于一种独特且研究不足的膜转运酶（Lutsenko等，2002），对于人体组织中的铜量代谢至关重要。编码这些蛋白质的ATP7A和ATP7B基因中的突变导致严重的遗传代谢疾病。迄今为止，尚未发表重金属转运ATPase的高分辨率结构。 将确定域的三维结构中ATP结合位点的位置。 在P型ATPases的催化循环的背景下，将研究ATP结合发生的构象变化，重点是将重金属转运ATPases与经过良好研究的CA2+-ATPase分开的独特特征。将确定威尔逊疾病和menkes疾病蛋白与主要结构的非同源区域相关的核苷酸结合结构域的三维结构的差异。该项目还将为未来的研究铜转移ATPases中引起疾病​​突变的结构影响提供基础，以解决Wilson和Menkes疾病蛋白的较大域的结构并映射结构域的相互作用表面。 迄今为止，Wilson病ATPase（WNABD）的N-核苷酸结合结构域（包括残基1036-1196）已以ATP结合形式解决（Dmitriev等，2006）。数据收集和处理，用于确定N-域（E1064A和H1069A）的两个引起疾病的突变变体的结构，进行了进展。1。Dmitriev，O.核苷酸结合环境和疾病突变的影响。纳特。学院。科学。美国A 103，5302-5307。 2。Lutsenko，S.，Efremov，R。G.，Tsivkovskii，R。和Walker，J。M.（2002）人类铜转运ATPase ATPase ATP7B（Wilson's Disease otein）：生化特性和调节J. Bioenerg。生物膜。 34，351-362。