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The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors.

eLife | 2017

Genetic and environmental factors, such as metals, interact to determine neurological traits. We reasoned that interactomes of molecules handling metals in neurons should include novel metal homeostasis pathways. We focused on copper and its transporter ATP7A because ATP7A null mutations cause neurodegeneration. We performed ATP7A immunoaffinity chromatography and identified 541 proteins co-isolating with ATP7A. The ATP7A interactome concentrated gene products implicated in neurodegeneration and neurodevelopmental disorders, including subunits of the Golgi-localized conserved oligomeric Golgi (COG) complex. COG null cells possess altered content and subcellular localization of ATP7A and CTR1 (SLC31A1), the transporter required for copper uptake, as well as decreased total cellular copper, and impaired copper-dependent metabolic responses. Changes in the expression of ATP7A and COG subunits in Drosophila neurons altered synapse development in larvae and copper-induced mortality of adult flies. We conclude that the ATP7A interactome encompasses a novel COG-dependent mechanism to specify neuronal development and survival.

Pubmed ID: 28355134 RIS Download

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM083144
  • Agency: NIEHS NIH HHS, United States
    Id: T32 ES012870
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK093386
  • Agency: NIH HHS, United States
    Id: P40 OD018537
  • Agency: NIEHS NIH HHS, United States
    Id: P30 ES019776
  • Agency: NINDS NIH HHS, United States
    Id: R21 NS088503

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This is a list of tools and resources that we have found mentioned in this publication.


ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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Enrichr (tool)

RRID:SCR_001575

A web-based gene list enrichment analysis tool that provides various types of visualization summaries of collective functions of gene lists. It includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results using the JavaScript library, Data Driven Documents (D3). The software can also be embedded into any tool that performs gene list analysis. System-wide profiling of genes and proteins in mammalian cells produce lists of differentially expressed genes / proteins that need to be further analyzed for their collective functions in order to extract new knowledge. Once unbiased lists of genes or proteins are generated from such experiments, these lists are used as input for computing enrichment with existing lists created from prior knowledge organized into gene-set libraries.

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PeptideAtlas (tool)

RRID:SCR_006783

Multi-organism, publicly accessible compendium of peptides identified in a large set of tandem mass spectrometry proteomics experiments. Mass spectrometer output files are collected for human, mouse, yeast, and several other organisms, and searched using the latest search engines and protein sequences. All results of sequence and spectral library searching are subsequently processed through the Trans Proteomic Pipeline to derive a probability of correct identification for all results in a uniform manner to insure a high quality database, along with false discovery rates at the whole atlas level. The raw data, search results, and full builds can be downloaded for other uses. All results of sequence searching are processed through PeptideProphet to derive a probability of correct identification for all results in a uniform manner ensuring a high quality database. All peptides are mapped to Ensembl and can be viewed as custom tracks on the Ensembl genome browser. The long term goal of the project is full annotation of eukaryotic genomes through a thorough validation of expressed proteins. The PeptideAtlas provides a method and a framework to accommodate proteome information coming from high-throughput proteomics technologies. The online database administers experimental data in the public domain. You are encouraged to contribute to the database.

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Cytoscape (tool)

RRID:SCR_003032

Software platform for complex network analysis and visualization. Used for visualization of molecular interaction networks and biological pathways and integrating these networks with annotations, gene expression profiles and other state data.

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NeuroMab (tool)

RRID:SCR_003086

A national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.

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Bloomington Drosophila Stock Center (tool)

RRID:SCR_006457

Collects, maintains and distributes Drosophila melanogaster strains for research. Emphasis is placed on genetic tools that are useful to a broad range of investigations. These include basic stocks of flies used in genetic analysis such as marker, balancer, mapping, and transposon-tagging strains; mutant alleles of identified genes, including a large set of transposable element insertion alleles; defined sets of deficiencies and a variety of other chromosomal aberrations; engineered lines for somatic and germline clonal analysis; GAL4 and UAS lines for targeted gene expression; enhancer trap and lacZ-reporter strains with defined expression patterns for marking tissues; and a collection of transposon-induced lethal mutations.

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Anti-Copper ATPase 1 (Menke's Disease Protein) Antibody (antibody)

RRID:AB_2062824

This monoclonal targets Copper ATPase 1 (Menke's disease protein)

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Fiji (software resource)

RRID:SCR_002285

Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.

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w[1118]; P{w[+mC]=Ddc-GAL4.L}Lmpt[4.36] (organism)

RRID:BDSC_7009

Drosophila melanogaster with name w[1118]; P{w[+mC]=Ddc-GAL4.L}Lmpt[4.36] from BDSC.

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w[1118]; PBac{w[+mC]=RB}Cog1[e02840]/TM6B, Tb[1] (organism)

RRID:BDSC_18089

Drosophila melanogaster with name w[1118]; PBac{w[+mC]=RB}Cog1[e02840]/TM6B, Tb[1] from BDSC.

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w[1118] (organism)

RRID:BDSC_5905

Drosophila melanogaster with name w[1118] from BDSC.

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DAVID (software resource)

RRID:SCR_003033

Bioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.

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RRID:SCR_014477

Software for identifying, characterizing, and quantifying proteins in biological samples. Can be used for range of proteomics workflows such as protein and peptide identification, PTM analysis, and isobaric mass tagging for quantification. Supports multiple database search algorithms and multiple dissociation techniques.

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HEK293T (cell line)

RRID:CVCL_0063

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SH-SY5Y (cell line)

RRID:CVCL_0019

Cell line SH-SY5Y is a Cancer cell line with a species of origin Homo sapiens (Human)

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