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

  1. Heather S Comstra
  2. Jacob McArthy
  3. Samantha Rudin-Rush
  4. Cortnie Hartwig
  5. Avanti Gokhale
  6. Stephanie A Zlatic
  7. Jessica B Blackburn
  8. Erica Werner
  9. Michael Petris
  10. Priya D'Souza
  11. Parinya Panuwet
  12. Dana Boyd Barr
  13. Vladimir Lupashin
  14. Alysia Vrailas-Mortimer  Is a corresponding author
  15. Victor Faundez  Is a corresponding author
  1. Emory University, United States
  2. Illinois State University, United States
  3. Agnes Scott College, United States
  4. University of Arkansas for Medical Sciences, United States
  5. 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.

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The following data sets were generated

Article and author information

Author details

  1. Heather S Comstra

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jacob McArthy

    School of Biological Sciences, Illinois State University, Normal, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Samantha Rudin-Rush

    Department of Chemistry, Agnes Scott College, Decatur, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Cortnie Hartwig

    Department of Chemistry, Agnes Scott College, Decatur, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Avanti Gokhale

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Stephanie A Zlatic

    Department of Cell Biology, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jessica B Blackburn

    Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Erica Werner

    Department of Biochemistry, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael Petris

    Department of Biochemistry, University of Missouri, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Priya D'Souza

    Department of Rollins School of Public Health, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Parinya Panuwet

    Department of Rollins School of Public Health, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Dana Boyd Barr

    Department of Rollins School of Public Health, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Vladimir Lupashin

    Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2350-1962
  14. Alysia Vrailas-Mortimer

    School of Biological Sciences, Illinois State University, Normal, United States
    For correspondence
    avraila@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  15. Victor Faundez

    Department of Cell Biology, Emory University, Atlanta, United States
    For correspondence
    vfaunde@emory.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2114-5271

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

  1. Andrew B West, University of Alabama at Birmingham, United States

Publication history

  1. Received: December 28, 2016
  2. Accepted: March 28, 2017
  3. Accepted Manuscript published: March 29, 2017 (version 1)
  4. Accepted Manuscript updated: April 5, 2017 (version 2)
  5. 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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  1. Heather S Comstra
  2. Jacob McArthy
  3. Samantha Rudin-Rush
  4. Cortnie Hartwig
  5. Avanti Gokhale
  6. Stephanie A Zlatic
  7. Jessica B Blackburn
  8. Erica Werner
  9. Michael Petris
  10. Priya D'Souza
  11. Parinya Panuwet
  12. Dana Boyd Barr
  13. Vladimir Lupashin
  14. Alysia Vrailas-Mortimer
  15. Victor Faundez
(2017)
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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