Crystal structures of the UBX domain of human UBXD7 and its complex with p97 ATPase

In humans, UBXD7 (also called UBXN7), an adaptor of p97 ATPase, can participate in the degradation of misfolded or damaged proteins in the p97-mediated ubiquitin proteasome system (UPS). UBXD7 binds to ubiquitinated substrates via its UBA domain and interacts with p97 N-terminal domain through its UBX domain to recruit p97 or the p97 core complex (p97/NPL4/UFD1). Here, we report the crystal structures of the UBX domain of UBXD7 (UBXD7UBX) at 2.0 Å resolution and its complex with p97 N-terminal domain (p97NTD-UBXD7UBX complex) at 2.4 Å resolution. A structural analysis and isothermal titration calorimetry results provide detailed molecular basis of interaction between UBXD7UBX and p97NTD. Moreover, structural superpositions suggest that dimerization of UBXD7UBX via an intermolecular disulfide bond could interfere with the formation of the p97NTD-UBXD7UBX complex. Interestingly, UBXD7 may have a cooperative effect on p97 interaction with UFD1. Together, these results provide structural and biochemical insights into the interaction between p97NTD and UBXD7UBX.