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CHAPERONE TARGET INTERACTIONS

陪伴目标互动

基本信息

批准号：
7690594
负责人：
Ninian J Blackburn
金额：
$ 28.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690594
关键词：
ATP phosphohydrolase Active Sites Affinity 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 orexin A receptor peptidylglycine alpha-amidating monooxygenase permease reconstitution stoichiometry structural biology synthetic peptide trafficking tumor growth uptake

项目摘要

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.

铜是真核生物必不可少的元素。由于在中等电位下易发生氧化还原化学反应