The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors
- Emory University, United States
- Illinois State University, United States
- Agnes Scott College, United States
- University of Arkansas for Medical Sciences, United States
- University of Missouri, United States
Abstract
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.
Data availability
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ATP7A IP DSP treated cells after incubation with BCS or CuCl2Available at the PeptideAtlas database.
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ATP7A IP Menkes and Rescued Menkes CellsAvailable at the PeptideAtlas database.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (NS088503)
- Victor Faundez
National Institute of Diabetes and Digestive and Kidney Diseases (DK093386)
- Michael Petris
National Institute of General Medical Sciences (GM083144)
- Vladimir Lupashin
National Institute of Environmental Health Sciences (P30 ES019776)
- Dana Boyd Barr
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Andrew B West, University of Alabama at Birmingham, United States
Publication history
- Received: December 28, 2016
- Accepted: March 28, 2017
- Accepted Manuscript published: March 29, 2017 (version 1)
- Accepted Manuscript updated: April 5, 2017 (version 2)
- Version of Record published: April 21, 2017 (version 3)
Copyright
© 2017, Comstra et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The interactome of the copper transporter ATP7A belongs to a network of neurodevelopmental and neurodegeneration factors
eLife 6:e24722.
https://doi.org/10.7554/eLife.24722
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