Regulation of Copper Homeostasis by COMMD proteins
COMMD 蛋白对铜稳态的调节
基本信息
- 批准号:9316602
- 负责人:
- 金额:$ 43.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-01 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:ANGPTL2 geneATP phosphohydrolaseActinsBiliaryBindingBiochemicalBiologyCoiled-Coil DomainComplexCopperDataDepositionDiseaseEarly EndosomeElementsEndosomesEnzymesEventExcretory functionF-ActinFamilyGenerationsGenesGenetic studyGoalsHomeostasisHomologous ProteinHumanIntestinal AbsorptionIntestinesKnockout MiceLaboratoriesMammalsMediatingMetabolismModelingMolecularMolecular ChaperonesMusPathway interactionsPlayProcessProtein FamilyProteinsProteomicsRecruitment ActivityRecyclingRegulationReportingRoleSet proteinSorting - Cell MovementSystemTimeTissuesTransition ElementsTransport VesiclesVesicleVesicle Transport PathwayWilson disease proteinWorkabsorptionextracellularhuman diseasein vivomembernotch proteinprotein functionreceptortraffickingtrans-Golgi Network
项目摘要
PROJECT SUMMARY
Copper (Cu) is an essential transition metal regulated by a complex set of transporters and chaperones.
Mammals rely on two related p-type ATPases, ATP7A and ATP7B, to regulate intracellular Cu levels and
coordinate its intestinal absorption and biliary excretion. Depending on Cu availability, ATP7A and ATP7B are
actively trafficked from trans-Golgi network (TGN) to cytosolic vesicles to mediate extracellular Cu excretion. At
the organismal level, ATP7A plays a required role in intestinal Cu absorption while of ATP7B is required for
biliary excretion. COMMD1, the founding member of a highly conserved family that includes 9 additional
members, has been long known to play a role in mammalian Cu metabolism.
R
ecent work from our
laboratories has uncovered that COMMD1 regulates the endosomal sorting of ATP7A.
This is mediated
through the formation of a complex containing CCDC22 and its homologous protein, CCDC93, termed the
COMMD/CCDC22/ CCDC93 or CCC complex. The CCC complex can exist in alternative configurations
depending on the recruitment of specific COMMD proteins. COMMD1-CCC binds to the WASH
complex, a
critical regulator of receptor trafficking within
the endo-lysosomal system. WASH activates the Arp2/3 complex,
leading to branched F-actin deposition on endosomes, a required step for the generation of transport vesicles
containing recycling cargo proteins such as ATP7A. In contrast, we recently reported that COMMD9-CCC
plays an essential role in the endosomal recycling of other proteins, such as Notch. Emerging data indicates
that COMMD9 also participates in ATP7A trafficking. However, it remains unclear how the CCC complex
regulates endosomal sorting and in which way do different COMMD-containing CCC complexes collaborate in
this process. The overall goal of this project is to provide a deep mechanistic understanding for the role of
COMMD proteins in endosomal sorting and their impact in Cu homeostasis. Our hypothesis is that the
primary function of the CCC complex is to regulate WASH activity. Furthermore, we hypothesize that different
COMMD proteins function to localize the CCC complex to different endosomal sub-compartments to mediate
cargo-specific effects and/or to regulate WASH activity along a continuum of sorting steps. The following
specific aims will be pursued: (1) To uncover the mechanism by which the CCC complex regulates WASH
activity. Here we will examine how CCC regulates F-Actin deposition on endosomes. (2) To understand the
contribution of the COMMD9-CCC complex in endosomal trafficking. Here we will examine mechanistically
how COMMD9 adds to the sorting process. (3) To assess the role of COMMD9 in cu homeostasis at the
organismal level. Here we will use tissue specific Commd9 knockout mice to study the role of this gene in Cu
metabolism in vivo. Altogether, the proposed studies will uncover critical aspects of vesicular sorting that have
wide ranging implications in biology and human disease, as well as examine these pathways and their impact
on Cu homeostasis.
项目总结
铜是一种重要的过渡金属,受一系列复杂的转运蛋白和伴侣调节。
哺乳动物依赖两个相关的p型ATPase,ATP7A和ATP7B来调节细胞内铜水平和
协调其肠道吸收和胆汁排泄。根据铜的可用性,ATP7A和ATP7B
主动地从跨高尔基网络(TGN)运输到胞液小泡,以调节细胞外铜的排泄。在…
在机体水平上,ATP7A在肠道铜吸收中起着必要的作用,而ATP7B在肠道铜吸收中起着必需的作用
胆汁排泄物。COMMD1,一个高度保守的家族的创始成员,包括另外9个
成员,很早以前就知道在哺乳动物的铜代谢中发挥作用。
R
我们最近的工作
实验室发现,COMMD1调节ATP7A的内体分类。
这是经过调解的
通过形成包含CCDC22及其同源蛋白CCDC93的复合体,称为
COMMD/CCDC22/CCDC93或CCC复合体。CCC复合体可以以替代构型存在
这取决于特定COMMD蛋白的招募。COMMD1-CCC结合到洗涤剂上
复杂,一个
受体转运的关键调节因子
内切溶酶体系统。WASH激活Arp2/3复合体,
导致内体上分支的F-肌动蛋白沉积,这是产生运输小泡的必要步骤
含有回收的货物蛋白,如ATP7A。相比之下,我们最近报道了COMMD9-CCC
在其他蛋白质的内体循环中起着至关重要的作用,如Notch。新兴数据表明
COMMD9也参与了ATP7A的贩运。然而,目前尚不清楚CCC复合体是如何
调节内体分选以及不同的含COMMD的CCC复合体以何种方式协作
这一过程。本项目的总体目标是为以下角色提供深入的机械理解
COMMD蛋白在内体分选中的作用及其对铜稳态的影响。我们的假设是
CCC复合体的主要功能是调节洗涤活动。此外,我们假设不同的
COMMD蛋白的功能是将CCC复合体定位到不同的内体亚室中进行调节
货物特定的影响和/或沿着分拣步骤的连续统一体调节洗涤活动。以下是
具体目标将被追求:(1)揭示CCC复合体调节洗涤的机制
活动。在这里,我们将研究CCC如何调节内体上F-肌动蛋白的沉积。(2)了解
COMMD9-CCC复合体在内体转运中的作用。在这里,我们将机械地检验
COMMD9如何添加到排序过程。(3)评估COMMD9在铜稳态中的作用。
生物体水平。在这里,我们将使用组织特异性的Commd9基因敲除小鼠来研究该基因在铜
体内代谢。总之,拟议的研究将揭示囊泡分选的关键方面
对生物学和人类疾病的广泛影响,以及研究这些途径及其影响
关于铜的动态平衡。
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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DANIEL D BILLADEAU其他文献
DANIEL D BILLADEAU的其他文献
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