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

Author:

Comstra Heather S1,McArthy Jacob2,Rudin-Rush Samantha3,Hartwig Cortnie3,Gokhale Avanti1,Zlatic Stephanie A1,Blackburn Jessica B4,Werner Erica5,Petris Michael6,D’Souza Priya7,Panuwet Parinya7,Barr Dana Boyd7,Lupashin Vladimir4ORCID,Vrailas-Mortimer Alysia2,Faundez Victor1ORCID

Affiliation:

1. Departments of Cell Biology, Emory University, Atlanta, United States

2. School of Biological Sciences, Illinois State University, Normal, United States

3. Department of Chemistry, Agnes Scott College, Decatur, Georgia

4. Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, United States

5. Department of Biochemistry, Emory University, Atlanta, United States

6. Department of Biochemistry, University of Missouri, Columbia, United States

7. Rollins School of Public Health, Emory University, Atlanta, 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.

Funder

National Institute of Neurological Disorders and Stroke

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of General Medical Sciences

National Institute of Environmental Health Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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