COPPER BINDING TO ALPHA-SYNUCLEIN, THE PARKINSON'S PROTEIN

铜与帕金森病蛋白 α-突触核蛋白的结合

• 批准号: 8362168
• 负责人: SERENA D DE BEER GEORGE
• 金额: $ 0.41万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362168
• 关键词: Affinity; Binding; Binding Sites; Chemistry; Copper; Disease; Environmental Risk Factor; Fluorescence; Funding; Grant; In Vitro; Ions; Laboratories; Ligands; Link; Metals; N-terminal; National Center for Research Resources; Neurodegenerative Disorders; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathology; Principal Investigator; Protein S; Proteins; Radiation; Research; Research Infrastructure; Resources; Role; Source; Structure; United States National Institutes of Health; Work; alpha synuclein; base; cost; insight; metal metabolism; mutant; protein complex; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. alpha-Synuclein (alpha-syn) has been implicated in the pathogenesis of a number of neurodegenerative diseases, the best known of which is Parkinson?s disease (PD). The sporadic form of PD has been linked to environmental factors that promote oxidative stress and aberrant redox-active metal metabolism, and metal-enhanced oligomerization of alpha-syn has been observed in vitro. Recent work in our laboratory has focused on the understanding the role of copper ions in the aggregation of alpha-syn. Our initial studies have shown that Cu(II) ions accelerate aggregation and that the copper ions are incorporated into alpha-syn, with the tightest affinity binding near the N-terminus (based on ICP-MS and fluorescence quenching). We propose Cu K-edge and EXAFS studies to examine the local structure of the Cu binding site in the WT protein and in related mutants. We will compliment these studies with XAS on synthetic N-terminal fragments in order to identify the Cu binding site ligands. Our studies will examine both Cu(II) and Cu(I) binding to the protein, as these results could potentially provide insights into the role of redox chemistry in alpha-syn pathology. Once the soluble Cu-protein complexes have been characterized, we are poised to examine alpha-syn fibrils generated in the presence of copper ions.

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