The copper-transporting ATPase, ATP7A is an eight-transmembrane protein crucial for normal human copper homeostasis. Mutations in ATP7A 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 was reported to cause distal motor neuropathy and the underlying disease mechanism was associated with an abnormal interaction with p97/VCP, a hexameric AAA ATPase with diverse biological functions. In this paper, we characterize the interaction and identify a concealed UBX domain in the third lumenal loop of ATP7A between the fifth and the sixth transmembrane domains. We show that T994I, located in the sixth transmembrane domain of ATP7A, results in conformational exposure of the UBX domain, which subsequently binds the N-terminal domain of p97/VCP. We show that the abnormal interaction occurs on the plasma membrane of cells. This represents the first report of p97/VCP binding to a UBX domain not normally exposed that results in an aberrant interaction with p97/VCP and adult-onset motor neuron degeneration.
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