Structure and function of the AAA + ATPase p97/Cdc48p

• p97/Cdc48p participates in various cellular pathways by functioning as a “segregase”.
• Mutations in p97 have been associated with various human diseases.
• Significant progress has been made in obtaining atomic resolution structures of p97 in different conformations.
• Controversy remains as to the mechanism underlying force generation by p97.

p97 (also known as valosin-containing protein (VCP) in mammals or Cdc48p in Saccharomyces cerevisiae) is an evolutionarily conserved ATPase present in all eukaryotes and archaebacteria. In conjunction with a collection of cofactors and adaptors, p97/Cdc48p performs an array of biological functions mostly through modulating the stability of ‘client’ proteins. Using energy from ATP hydrolysis, p97/Cdc48p segregates these molecules from immobile cellular structures such as protein assemblies, membrane organelles, and chromatin. Consequently, the released polypeptides can be efficiently degraded by the ubiquitin proteasome system or recycled. This review summarizes our current understanding of the structure and function of this essential cellular chaperoning system.