A Mighty “Protein Extractor” of the Cell: Structure and Function of the p97/CDC48 ATPase

Abstract

p97/VCP (known as Cdc48 in S. cerevisiae or TER94 in Drosophila) is one of the most abundant cytosolic ATPases. It is highly conserved from archaebacteria to eukaryotes. In conjunction with a large number of cofactors and adaptors, it couples ATP hydrolysis to segregation of polypeptides from immobile cellular structures such as protein assemblies, membranes, ribosome, and chromatin. This often results in proteasomal degradation of extracted polypeptides. Given the diversity of p97 substrates, this “segregase” activity has profound influence on cellular physiology ranging from protein homeostasis to DNA lesion sensing, and mutations in p97 have been linked to several human diseases. Here we summarize our current understanding of the structure and function of this important cellular machinery and discuss the relevant clinical implications.

Proteomics of SARS-CoV-2-infected host cells reveals therapy targets

“…Therefore, we tested the effects of proteostasis perturbation on SARS-CoV-2 replication using NMS-873, a small molecule inhibitor of the AAA ATPase p97. p97 is a key component of proteostasis affecting protein degradation, membrane fusion, vesicular trafficking and disassembly of stress granules 27 . NMS-873 has been shown to inhibit influenza A and B replication previously 28 .…”

Protein translocation by the SecA ATPase occurs by a power‐stroke mechanism

“…Examples include hexameric ATPases, such as the p97 ATPase (Cdc48 in yeast), which extracts proteins from membranes or tight complexes, the Clp's and the ATPases of the 26S proteasome, which push polypeptides into a proteolytic chamber, and the NSF protein, which disassembles SNARE complexes involved in membrane fusion (for review, see Zhao et al, 2007;Bodnar & Rapoport, 2017;Ye et al, 2017;Yedidi et al, 2017). Examples include hexameric ATPases, such as the p97 ATPase (Cdc48 in yeast), which extracts proteins from membranes or tight complexes, the Clp's and the ATPases of the 26S proteasome, which push polypeptides into a proteolytic chamber, and the NSF protein, which disassembles SNARE complexes involved in membrane fusion (for review, see Zhao et al, 2007;Bodnar & Rapoport, 2017;Ye et al, 2017;Yedidi et al, 2017).…”

“…Many processes in the cell involve AAA family ATPases that perform mechanical work to remodel or relocate proteins. Examples include hexameric ATPases, such as the p97 ATPase (Cdc48 in yeast), which extracts proteins from membranes or tight complexes, the Clp's and the ATPases of the 26S proteasome, which push polypeptides into a proteolytic chamber, and the NSF protein, which disassembles SNARE complexes involved in membrane fusion (for review, see Zhao et al, 2007;Bodnar & Rapoport, 2017;Ye et al, 2017;Yedidi et al, 2017). Another important member of this ATPase family is SecA, which translocates polypeptides through the plasma membrane in bacteria (for review, see Corey et al, 2016;Rapoport et al, 2017;Cranford-Smith & Huber, 2018).…”

Valosin-containing protein VCP/p97 is essential for the intracellular development of Leishmania and its survival under heat stress

“…It plays a key role in multiple protein quality control pathways mediated by the Ubiquitin Proteasome System and is implicated in the maintenance of cellular proteostasis (Franz, Ackermann, & Hoppe, 2014;Meyer, Bug, & Bremer, 2012;van den Boom & Meyer, 2017). In all these pathways, VCP/p97 hydrolyses adenosine triphosphate (ATP) and uses the resulting energy to extract or disassemble polyubiquitinated substrates from membranes, organelles, chromatin, or in general from large protein assemblies and deliver them to the 26S proteasome for degradation (Bodnar & Rapoport, 2017b;Christianson & Ye, 2014;Ye, Tang, Zhang, & Xia, 2017). VCP/p97 is indeed involved in the extraction of ubiquitylated proteins from the endoplasmic reticulum associated protein degradation (ERAD; Qi, Tsai, & Arvan, 2017;Wolf & Stolz, 2012) and similarly in the translocation of damaged mitochondrial proteins from the outer mitochondrial membrane into the cytosol (associated degradation; (Heo et al, 2010;Taylor & Rutter, 2011), the ribosome quality control (Brandman et al, 2012), the removal of chromatin-bound proteins (Franz, Ackermann, & Hoppe, 2016), genome stability (Vaz, Halder, & Ramadan, 2013), stress granules clearance (Buchan, Kolaitis, Taylor, & Parker, 2013), and the removal of damaged lysosomes by autophagy (Papadopoulos et al, 2017).…”