Interaction between the AAA ATPase p97/VCP and a concealed UBX domain in the copper transporter ATP7A is associated with motor neuron degeneration [Cell Biology]

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 trans-Golgi network. Using protein MS, we identified potential coordinating components of the ATP7AT994I–p97 complex, including NSFL1 cofactor (NSF1C or p47) that may be relevant to the pathophysiology and clinical effects associated with ATP7AT994I. Our study represents the first report of p97/VCP binding to a UBX domain that is not normally exposed, resulting in an aberrant protein–protein interaction leading to motor neuron degeneration.
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research