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CTR家族
介导细胞铜摄取。同样,铜转运ATP酶和细胞内铜的作用
在铜分泌和铜离子转移到铜酶的活性位点中的分子伴侣已经被
牢固确立。仍然难以理解的是,这些不同的成分是如何在分子水平上整合的。
水平,主要是因为参与这些过程的膜蛋白的结构是未知的。
该项目的长期目标是在结构层面上了解铜
转运膜蛋白和细胞铜分子伴侣相互作用,
细胞内铜的定向流动。
实现目标1的工作利用了我们在人高亲和力多肽的结构测定方面的进展。
铜转运蛋白hCTR 1。该结构表明hCTR 1三聚体中C-末端的聚集
为铜离子和铜分子伴侣创造了一个结合位点,这将允许直接转移
铜从hCTR 1转移到分子伴侣。值得注意的是,形成该位点的氨基酸残基在哺乳动物中不存在。
哺乳动物的CTR 2,提出了一个问题,是否所有的CTR蛋白质使用相同的机制来分配
铜到下游受体。我们建议通过电子晶体学解析hCTR 2的结构,
研究hCTR 2中一组替代的金属结合残基可以在功能上取代
在hCTR 1中观察到的C-末端分子伴侣对接位点
CTR:分子伴侣相互作用,目的2的目标是捕获CTR:分子伴侣复合物,并可视化它们的相互作用。
用电子显微镜单粒子方法进行结构化。最后,目标3的长期目标是
铜转运ATP酶7 B的结构,其参与铜分泌。的关键方面
这些研究将描述包埋在细胞膜和细胞质之间的空间关系。
这些结构域对于ATP酶的复杂运输行为的功能和调节至关重要。
项目成果
期刊论文数量(0)
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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
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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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