CHAPERONE TARGET INTERACTIONS

陪伴目标互动

• 批准号: 8379464
• 负责人: Ninian J Blackburn
• 金额: $ 25.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8379464
• 关键词: ATP phosphohydrolase; Active Sites; Affinity; Alzheimer' s Disease; Antioxidants; Ataxia; Binding; Binding Sites; Biogenic Amine Metabolism; C-terminal; Carrier Proteins; Cells; Chemistry; Collaborations; Comparative Study; Complex; Connective Tissue; Copper; Coupled; Cysteine; Defect; Development; Disease; Disulfides; Endocrine Gland Neoplasms; Enzymes; Eukaryota; Failure; Funding; Gene Mutation; Genes; Grant; Hand; Health; Hepatolenticular Degeneration; Homeostasis; Human; Indium; Ions; Iron; Label; Laboratories; Ligation; Link; Malignant Neoplasms; Measures; Mediating; Membrane; Menkes Kinky Hair Syndrome; Metals; Methodology; Methods; Molecular; Molecular Chaperones; Monitor; Mutagenesis; Neurodegenerative Disorders; Neuropeptides; Neurotransmitters; Organism; Oxidation-Reduction; Pathology; Pathway interactions; Peptides; Pigmentation physiologic function; Plasmids; Play; Process; Proteins; Recruitment Activity; Regulation; Respiration; Roentgen Rays; Role; Route; Secretory Vesicles; Selenium; Selenocysteine; Selenomethionine; Senile Plaques; Side; Site; Spectrum Analysis; Structure; System; Techniques; Technology; Testing; Wilson disease protein; absorption; base; cancer therapy; cancer type; copper-transporting ATPase; design; enzyme activity; hormone biosynthesis; innovation; intermolecular interaction; meetings; mutant; novel; peptidylglycine alpha-amidating monooxygenase; permease; reconstitution; stoichiometry; structural biology; synthetic peptide; trafficking; tumor growth; uptake

Copper is an essential element in eukaryotic organisms. Due to facile redox chemistry at moderate potentials, it functions at the active sites of many critical enzymes involved in a wide variety of processes, including neurotransmitter and neuropeptide hormone biosynthesis, biogenic amine metabolism and connective tissue formation, pigmentation, respiration, and antioxidant defense. New findings have linked certain cancers to copper mediated enzyme activity, for example the observation that the expression of the cuproenzyme PAM in endocrine tumors mediates tumor growth. Another intriguing link of importance to cancer therapy, is the recruitment of the CTR1 high affinity copper transporter in the uptake of cis-platin into cells by a presently unknown mechanism. Because copper is both essential and potentially toxic, cells have evolved complex molecular machinery to maintain levels within a narrow range of concentration, and failure to achieve liomeostasis results in diseases related to either Cu deficiency or excess which include those involving genetic mutations in the copper transporting ATPases, ATP7A (Menkes disease) and ATP7B (Wilson disease). Important consequences of aberrant copper homeostasis have also been implicated in neurodegenerative disorders, and in the pathology of amyloid plaque formation in Alzheimers. Therefore, the study of copper uptake, transport and trafficking is of great importance to human health. In eukaryotes, copper is imported by the membrane associated high affinity transporter CTR1, and thence distributed to target proteins via metallochaperone shuttles. An important tenet of copper homeostasis is the hypothesis that CTR1 hands off copper to the chaperones which in turn transport the metal to its sites of action. However, the interaction of CTR1 with chaperones has not yet been experimentally verified. Project 2 of the PPG will therefore leverage recent advances in the structural biology of hCTRl to investigate (i) the mode of copper binding to CTR1, (ii) the interaction of CTR1 with the chaperone hCCS, and (iii) the mechanisms by which chaperones and ATPases interact with and transfer copper to their target cuproenzymes. The technique of selenium-labeling coupled to X-ray absorption spectroscopy (developed in the last grant period) will be used extensively in these studies.

铜是真核生物中的重要元素。由于中等电位的轻松氧化还原化学，它 许多关键酶的活动地点的功能，包括各种过程，包括 神经递质和神经肽激素生物合成，生物胺代谢和结缔组织 形成，色素沉着，呼吸和抗氧化剂防御。新发现将某些癌症与 铜介导的酶活性，例如观察到库酶PAM在 内分泌肿瘤介导肿瘤的生长。重要性与癌症治疗的另一个有趣的联系是 CTR1高亲和力铜转运蛋白在顺铂摄入细胞中的募集 未知机制。因为铜既是必不可少的，也是潜在的毒性，所以细胞已经进化了复合物 分子机械以保持浓度范围内的水平，并且无法实现 liomeostasis会导致与Cu缺乏或过量有关的疾病，包括涉及遗传的疾病 运输ATPases，ATP7A（Menkes病）和ATP7B（Wilson Disea）的铜中突变。 异常铜稳态的重要后果也与神经退行性有关 疾病，以及阿尔茨海默氏症中淀粉样菌斑形成的病理学。因此，铜的研究 吸收，运输和贩运对人类健康至关重要。在真核生物中，铜是由 膜相关的高亲和力转运蛋白CTR1，然后通过 金属伴侣班车。铜稳态的重要宗旨是Ctr1取消的假设 铜到伴侣，然后将金属传输到其作用位置。但是，相互作用 带有伴侣的CTR1尚未经过实验验证。因此，PPG的项目2将利用 HCTRL结构生物学的最新进展研究（i）铜结合与Ctr1的模式，（ii） CTR1与伴侣HCC的相互作用，以及（iii）伴侣和ATPases的机制 与铜相互作用并将其转移到目标库酶。硒标签的技术耦合到 在这些研究中，将广泛使用X射线吸收光谱（在最后一个赠款时期开发）。