Valosin-containing protein

3EBB, 3HU1, 3HU2, 3HU3, 3QC8, 3QQ7, 3QQ8, 3QWZ, 3TIW, 4KDI, 4KDL, 4KLN, 4KO8, 4KOD, 4P0A, 5C19, 3CF2, 3CF1, 5FTK, 5C18, 3CF3, 5FTJ, 5FTM, 5FTL, 5FTN, 5C1B, 5C1A, 5DYI, 5DYG7415269523ENSG00000165280ENSMUSG00000028452P55072Q01853NM_007126NM_001354927NM_001354928NM_009503NP_009057NP_001341856NP_001341857NP_033529Transitional endoplasmic reticulum ATPase (TER ATPase) also known as valosin-containing protein (VCP) or p97 in mammals and CDC48 in S. Cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.1e32: STRUCTURE OF THE N-TERMINAL DOMAIN AND THE D1 AAA DOMAIN OF MEMBRANE FUSION ATPASE P971oz4:1r7r: The crystal structure of murine p97/VCP at 3.6A1s3s: Crystal structure of AAA ATPase p97/VCP ND1 in complex with p47 C2pjh: Structural Model of the p97 N domain- npl4 UBD complex Transitional endoplasmic reticulum ATPase (TER ATPase) also known as valosin-containing protein (VCP) or p97 in mammals and CDC48 in S. Cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome. p97/CDC48 is a member of the AAA+ (extended family of ATPases associated with various cellular activities) ATPase family. Enzymes of this family are found in all species from bacteria to humans. Many of them are important chaperones that regulate folding or unfolding of substrate proteins. p97/CDC48 is a type II AAA+ ATPase, which means that it contains two tandem ATPase domains (named D1 and D2, respectively) (Figure 1). The two ATPase domains are connected by a short polypeptide linker. A domain preceding the D1 domain (N-terminal domain) and a short carboxyl-terminal tail are involved in interaction with cofactors. The N-domain is connected to the D1 domain by a short N-D1 linker. Most known substrates of p97/CDC48 are modified with ubiquitin chains and degraded by the 26S proteasome. Accordingly, many p97/CDC48 coenzymes and adaptors have domains that can recognize ubiquitin. It has become evident that the interplays between ubiquitin and p97/CDC48 cofactors are critical for many of the proposed functions, although the precise role of these interactions remains to be elucidated. CDC48 was discovered in a genetic screen for genes involved in cell cycle regulation in budding yeast. The screen identified several alleles of Cdc48 that affects cell growth at non-permissive temperatures. The mammalian homolog of CDC48 was initially characterized as a 97 kDa protein precursor for the small peptide valosin. It was therefore named as valosin-containing protein (VCP) or p97, but subsequent studies showed that valosin is an artifact of purification unrelated to p97. Nevertheless, the VCP nomenclature is still being used in the literature. p97/CDC48 is one of the most abundant cytoplasmic proteins in eukaryotic cells. It is ubiquitously expressed in all tissues in multicellular organisms. In humans, the mRNA expression of p97 was found to be moderately elevated in certain types of cancer. In mammalian cells, p97 is predominantly localized to the cytoplasm, and a significant fraction is associated to membranes of cellular organelles such as the endoplasmic reticulum (ER), Golgi, mitochondria, and endosomes. The subcellular localization of CDC48 has not been fully characterized, but is likely to be similar to the mammalian counterpart. A fraction of p97/CDC48 was also found in the nucleus. According to the crystal structures of full-length wild-type p97, six p97 subunits assemble into a barrel-like structure, in which the N-D1 and D2 domains form two concentric, stacked rings (Figure 2). The N-D1 ring is larger (162 Å in diameter) than the D2 ring (113 Å) due to the laterally attached N-domains. The D1 and D2 domains are highly homologous in both sequence and structure, but they serve distinct functions. For example, the hexameric assembly of p97 only requires the D1 but not the D2 domain. Unlike many bacterial AAA+ proteins, assembly of p97 hexamer does not depend on the presence of nucleotide. The p97 hexameric assembly can undergo dramatic conformational changes during nucleotide hydrolysis cycle, and it is generally believed that these conformational changes generate mechanical force, which is applied to substrate molecules to influence their stability and function. However, how precisely p97 generates force is unclear.