The Cdc48 machine in endoplasmic reticulum associated protein degradation

• Published in: Biochimica et biophysica acta Vol. 1823; no. 1; pp. 117 - 124
• Main Authors: Wolf, Dieter H., Stolz, Alexandra
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2012
• Subjects: AAA-type ATPase; Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - metabolism; adenosine triphosphate; adenosinetriphosphatase; Animals; Cdc48; Cdc48–Ufd1–Npl4 complex; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - metabolism; endoplasmic reticulum; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum-Associated Degradation; ER-associated protein degradation (ERAD); eukaryotic cells; Humans; hydrolysis; lectins; mammals; membrane proteins; Multiprotein Complexes - chemistry; Multiprotein Complexes - metabolism; p97/VCP; proteasome endopeptidase complex; Protein Binding; protein degradation; protein folding; Protein Structure, Quaternary; Protein Structure, Tertiary; Protein Unfolding; proteinases; Ubiquitin–proteasome-system (UPS); Valosin Containing Protein; ER-associated protein degradation (ERAD); Cdc48; p97/VCP; Cdc48–Ufd1–Npl4 complex; Ubiquitin–proteasome-system (UPS); AAA-type ATPase
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2011.09.002

The AAA-type ATPase Cdc48 (named p97/VCP in mammals) is a molecular machine in all eukaryotic cells that transforms ATP hydrolysis into mechanic power to unfold and pull proteins against physical forces, which make up a protein's structure and hold it in place. From the many cellular processes, Cdc48 is involved in, its function in endoplasmic reticulum associated protein degradation (ERAD) is understood best. This quality control process for proteins of the secretory pathway scans protein folding and discovers misfolded proteins in the endoplasmic reticulum (ER), the organelle, destined for folding of these proteins and their further delivery to their site of action. Misfolded lumenal and membrane proteins of the ER are detected by chaperones and lectins and retro-translocated out of the ER for degradation. Here the Cdc48 machinery, recruited to the ER membrane, takes over. After polyubiquitylation of the protein substrate, Cdc48 together with its dimeric co-factor complex Ufd1–Npl4 pulls the misfolded protein out and away from the ER membrane and delivers it to down-stream components for degradation by a cytosolic proteinase machine, the proteasome. The known details of the Cdc48–Ufd1–Npl4 motor complex triggered process are subject of this review article. This article is part of a Special Issue entitled: AAA ATPases: Structure and function. ►Cdc48 is a type II AAA-type ATPase with two ATP binding domains. ►From the many cellular functions of Cdc48 its involvement in ERAD is understood best. ►Cdc48 function is driven by several substrate recruiting and substrate processing co-factors. ►Cdc48 is a molecular motor with ratcheting and segregase activity.