A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. Cdc48/p97 consists of an N-terminal (N) domain and two ATPase domains (D1 and D2). Crystal and cryo-electron microscopy (cryo-EM) structures of p97 show that the D1 and D2 ATPase domains form stacked hexameric rings, with a “cis” and a “trans” side. Cdc48/p97 cooperates with a variety of protein cofactors; some of these determine substrate specificity and others trim or extend the ubiquitin chain attached to the substrate. The exact functions of these cofactors are poorly understood. Many cofactors bind to the N domain of Cdc48/p97, but some associate with the C-terminal tail. 
One of the most important cofactors is the Ufd1/Npl4 (UN) heterodimer, which participates in many Cdc48-dependent processes, including ERAD. Cdc48/p97 is generally thought to function upstream of the proteasome, handling substrates that ultimately are destined for proteasomal degradation. Many of the substrate molecules released from Cdc48 contain four or more ubiquitin molecules, which would be a suitable targeting signal for the proteasome, provided that ubiquitin molecules emerging from the D2 ring rapidly refold. At least in the case of ERAD, substrates do not directly bind to the proteasome but rather first interact with Rad23 or Dsk2. Some substrates may be transferred directly from Cdc48 into the 20S proteasome without involvement of the 19S subunit. The reasons why p97 disease mutations are deleterious remain ambiguous.

References

1.Bodnar N, Rapoport T. F1000Res. 2017;6:1318.