ArticleThe Journal of biological chemistry2018
Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- A functional framework in patient fibroblasts informs ATP7A variant pathogenicity and identifies p.Q990P as a novel cause of distal motor neuropathy.Human molecular genetics · 2026Article
- Copper restriction unmasks axonal degeneration in a mouse model of X-linked hereditary motor neuropathy.Metallomics : integrated biometal science · 2026Article
- Copper Homeostasis and Cuproptosis in Neurological Disorders.Drug design, development and therapy · 2026Review
- Intravenous AAV9-Science advances · 2025Article
- Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.Molecular neurodegeneration · 2023Review
- The M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease.Neurobiology of disease · 2021Article
- Genes, the brain, and artificial intelligence in evolution.Journal of human genetics · 2021Review
- The molecular mechanisms of copper metabolism and its roles in human diseases.Pflugers Archiv : European journal of physiology · 2020Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The copper-transporting ATPase ATP7A contains eight transmembrane domains and is required for normal human copper homeostasis. Mutations in the ATP7A gene may lead to infantile-onset cerebral degeneration (Menkes disease); occipital horn syndrome (OHS), a related but much milder illness; or an adult-onset isolated distal motor neuropathy. The ATP7A missense mutation T994I is located in the sixth transmembrane domain of ATP7A, represents one of the variants associated with the latter phenotype, and is associated with an abnormal interaction with p97/valosin-containing protein (VCP), a hexameric AAA ATPase (ATPase associated with diverse cellular activities) with multiple biological functions. In this study, we further characterized this interaction and discovered a concealed UBX domain in the third lumenal loop of ATP7A, between its fifth and sixth transmembrane domains. We show that the T994I substitution results in conformational exposure of the UBX domain, which then binds the N-terminal domain of p97/VCP. We also show that this abnormal interaction occurs at or near the cell plasma membrane. The UBX domain has a conserved hydrophobic FP (Phe-Pro) motif, and substitution with di-alanine abrogated the interaction and restored the proper intracellular localization of ATP7A in the
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