STRUCTURAL BIOLOGY OF COPPER HOMEOSTASIS
铜稳态的结构生物学
基本信息
- 批准号:7690563
- 负责人:
- 金额:$ 27.75万
- 依托单位:
- 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:
- 关键词:ATP phosphohydrolaseActive SitesAddressAffinityAlzheimer&aposs DiseaseAmino AcidsAntineoplastic AgentsAreaBehaviorBindingBinding SitesBiochemicalBiologyC-terminalCell physiologyCell secretionCellsCisplatinComplexCopperCreutzfeldt-Jakob SyndromeCrystallizationCuesDataDiseaseDockingElectronsEngineeringFamilyGeneticGlycophorin AGoalsHomeostasisHumanIonsLettersLightLinkMediatingMembraneMembrane ProteinsMembrane Transport ProteinsMenkes Kinky Hair SyndromeMetalsMethodsMicroscopicMolecularMolecular ChaperonesMusParkinson DiseasePhysiologicalProcessProteinsRegulationResolutionRoleSamplingSiteStructureTestingWilson disease proteinWorkYeastsbasecopper-transporting ATPasecrosslinkelectron crystallographygenetic regulatory proteinin vivoinsightmetalloenzymeneuropathologynovelorexin A receptororexin B receptorparticlereconstructionresponsespatial relationshipstructural biologytooltraffickinguptake
项目摘要
Genetic and biochemical studies lend strong support to the idea that the CTR-family of membrane proteins
mediate cellular copper uptake. Similarly, the roles of copper transporting ATPases and intracellular copper
chaperones in copper secretion and transfer of copper ions to the active sites of cuproenzymes have been
firmly established. What remains elusive, is how these different components are integrated at the molecular
level, largely because the structures of the membrane proteins involved in these processes are unknown.
The longterm goal of this project is to understand at a structural level the mechanism by which copper
transporting membrane proteins and cellular copper chaperones interact with each other to accomplish
directed flow of copper within cells.
Work towards Aim 1 capitalizes on our progress in the structure determination of the human high affinity
copper transporter hCTR1. The structure suggests that clustering of the C-termini in the hCTR1 trimer
creates a binding site for both copper ions and copper chaperones, which would allow for a direct transfer of
copper from hCTR1 to the chaperones. Notably, the amino acid residues forming this site are absent in
mammalian CTR2, raising the question whether all CTR-proteins use the same mechanism to distribute
copper to downstream acceptors. We propose to solve the structure of hCTR2 by electron crystallography to
investigate the hypothesis that in hCTR2 an alternate set of metal binding residues can functionally replace
the C-terminal chaperone docking site observed in hCTRl Further pursuing the idea of direct
CTR:chaperone interactions, the goal of Aim 2 is to trap CTR:chaperone complexes, and to visualize their
structure by electron microscopic single particle methods. Finally, the longterm goal for Aim 3 is to solve the
structure of the copper transporting ATPase 7B, which is involved in copper secretion. The key aspect of
these studies will be to delineate the spatial relationships between the membrane embedded and cytosolic
domains that are critical for function and the regulation of the ATPase's complex trafficking behavior.
遗传和生物化学研究有力地支持了膜蛋白的cr家族
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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VINZENZ UNGER其他文献
VINZENZ UNGER的其他文献
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{{ truncateString('VINZENZ UNGER', 18)}}的其他基金
Structure and Function of Mammalian Copper Transporters
哺乳动物铜转运蛋白的结构和功能
- 批准号:
9353441 - 财政年份:2016
- 资助金额:
$ 27.75万 - 项目类别:
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