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. Mutations in p97/VCP itself have been associated with diverse inherited motor neuron diseases including ALS and CMT2. We characterized the ATP7A-p97/VCP interaction and identified 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 represented 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. Recently, we identified two isolated distal motor neuropathy families with other missense alleles in the same transmembrane segment of ATP7A as T994I, one of which (A998V) also interacts strongly with p97/VCP, highlighting the critical importance of p97/VCP loss-of-function in motor neuron degeneration.
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