Valosin-containing protein

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Valosin containing protein
Protein VCP PDB 1e32.png
PDB rendering based on 1e32.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols VCP ; ALS14; HEL-220; HEL-S-70; IBMPFD; IBMPFD1; TERA; p97
External IDs OMIM601023 MGI99919 HomoloGene5168 ChEMBL: 1075145 GeneCards: VCP Gene
EC number
RNA expression pattern
PBB GE VCP 208649 s at tn.png
PBB GE VCP 208648 at tn.png
More reference expression data
Species Human Mouse
Entrez 7415 269523
Ensembl ENSG00000165280 ENSMUSG00000028452
UniProt P55072 Q01853
RefSeq (mRNA) NM_007126 NM_009503
RefSeq (protein) NP_009057 NP_033529
Location (UCSC) Chr 9:
35.06 – 35.07 Mb
Chr 4:
42.98 – 43 Mb
PubMed search [1] [2]

Transitional endoplasmic reticulum ATPase (TER ATPase) also known as valosin-containing protein (VCP) or CDC48 in S. Cerevisiae is an enzyme that in humans is encoded by the VCP gene.[1][2][3] 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.[4] 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.[5] 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.[6] 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,[7] 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.

Tissue and subcelluar distribution[edit]

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.[5]

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.[8][9][2][10][11] 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.[12]


According to the crystal structures of full-length wild-type p97,[13][14] 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.[15] 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,[16][17][18][19][20] 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.

The ATP hydrolysis cycle[edit]

The ATP hydrolyzing activity is indispensable for the p97/CDC48 functions. [21] The two ATPase domains of p97 (D1 and D2) are not equivalent because the D2 domain displays higher ATPase activity than the D1 domain in wild-type protein. Nevertheless, their activities are dependent of each other.[22][23][24][25] For example, nucleotide binding to the D1 domain is required for ATP binding to the D2 domain and nucleotide binding and hydrolysis in D2 is required for the D1 domain to hydrolyze ATP.

The ATPase activity of p97 can be influenced by many factors. For example, it can be stimulated by heat[25] or by a putative substrate protein.[26] Association with cofactors can have either positive or negative impact on the p97 ATPase activity.[27][28]

Mutations in p97 can also influence its activity. For example, p97 mutant proteins carrying single point mutations found in patients with IBMPFD (inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia) (see below) have 2-3fold increase in ATPase activity.[23][29][30]

p97/CDC48-interacting proteins[edit]

Recent proteomic studies have identified a large number of p97-interacting proteins. Many of these proteins serve as adaptors that link p97/CDC48 to a particular subcellular compartment to function in a specific cellular pathway. Others function as adaptors that recruit substrates to p97/CDC48 for processing. Some p97-interacting proteins are also enzymes such as N-glycanase, ubiquitin ligase, and deubiquitinase, which assist p97 in processing substrates.

Most cofactors bind p97/CDC48 through its N-domain, but a few interact with the short carboxy-terminal tail in p97/CDC48. Representative proteins interacting with the N-domain are Ufd1, Npl4, p47 and FAF1.[31][32][33] Examples of cofactors that interact with the carboxy-terminal tail of p97 are PLAA, PNGase, and Ufd2.[34][35][36]

The molecular basis for cofactor binding has been studied for some cofactors that interact with the p97 N-domain. The N-domain consists of two sub-domains of roughly equal size: the N-terminal double Y-barrel and a C-terminal b-barrel (Figure 3). Structural studies show that many cofactor proteins bind to the N-domain at a cleft formed between the two sub-domains.

Among those that bind to the N-domain of p97, two most frequently occurring sequence motifs are found: one is called UBX motif (ubiquitin regulatory X)[37] and the other is termed VIM (VCP-interacting motif).[38] The UBX domain is a 80-residue module with a fold highly resembling the structure of ubiquitin. The VCP-interacting motif (VIM) is a linear sequence motif (RX5AAX2R) found in a number of p97 cofactors including gp78,[39] SVIP (small VCP-inhibiting protein)[40] and VIMP (VCP interacting membrane protein).[41] Although the UBX domain uses a surface loop whereas the VIM forms a a-helix to bind p97, both UBX and VIM bind at the same location between the two sub-domains of the N-domain (Figure 3).[42] It was proposed that hierarchical binding to distinct cofactors may be essential for the broad functions of p97/CDC48.[43][44]


p97/CDC48 performs diverse functions through modulating the stability and thus the activity of its substrates. The general function of p97/CDC48 is to segregate proteins from large protein assembly or immobile cellular structures such as membranes or chromatin, allowing the released protein molecules to be degraded by the proteasome. The functions of p97/CDC48 can be grouped into the following three major categories.

Protein quality control[edit]

The best characterized function of p97 is to mediate a network of protein quality control processes in order to maintain protein homeostasis.[45] These include endoplasmic reticulum-associated protein degradation (ERAD) and mitochondria-associated degradation.[10][46] In these processes, ATP hydrolysis by p97/CDC48 is required to extract aberrant proteins from the membranes of the ER or mitochondria. p97/CDC48 is also required to release defective translation products stalled on ribosome in a process termed ribosome-associated degradation.[47][48][49] It appears that only after extraction from the membranes or large protein assembly like ribosome, can polypeptides be degraded by the proteasome. In addition to this ‘segregase’ function, p97/CDC48 might have an additional role in shuttling the released polypeptides to the proteasome. This chaperoning function seems to be particularly important for degradation of certain aggregation-prone misfolded proteins in nucleus.[50] Several lines of evidence also implicate p97 in autophagy, a process that turns over cellular proteins (including misfolded ones) by engulfing them into double-membrane-surrounded vesicles named autophagosome, but the precise role of p97 in this process is unclear.[51]

Chromatin-associated functions[edit]

p97 also functions broadly in eukaryotic nucleus by releasing protein molecules from chromatins in a manner analogous to that in ERAD.[52] The identified p97 substrates include transcriptional repressor α2 and RNA polymerase (Pol) II complex and CMG DNA helicase in budding yeast, and the DNA replicating licensing factor CDT1, DNA repairing proteins DDB2 and XPC, mitosis regulator Aurora B, and certain DNA polymerases in mammalian cells. These substrates link p97 function to gene transcription, DNA replication and repair, and cell cycle progression.

Membrane fusion and trafficking[edit]

Biochemical and genetic studies have also implicated p97 in fusion of vesicles that lead to the formation of Golgi apparatus at the end of mitosis.[53] This process requires the ubiquitin binding adaptor p47 and a p97-associated deubiquitinase VCIP135, and thus connecting membrane fusion to the ubiquitin pathways. However, the precise role of p97 in Golgi formation is unclear due to lack of information on relevant substrate(s). Recent studies also suggest that p97 may regulate vesicle trafficking from plasma membrane to the lysosome, a process termed endocytosis.[51]

Clinical significance[edit]

p97 has received much attention recently also because genetics studies have linked mutations in p97 to pathogenesis of several human diseases such as IBMPFD and amyotrophic lateral sclerosis (ALS).[54][55]

IBMPFD (OMIM 167320) is an autosomal dominant, progressive, debilitative and ultimately fatal disorder.[56] It is a late-onset disease with initial symptoms typically appearing in adulthood. The disease mainly affects one or more of the following three tissue types: the muscle (myopathy), the bones (Paget’s disease of the bone), and the brain (frontotemporal dementia). Among them, myopathy is the most common clinical menifestation found in about 85% of IBMPFD patients; the bone pathology is observed in about half of the patients; and frontotemporal dementia occurs in approximately one-third of all cases.

Phenotypic characterization of IBMPFD patient muscle tissue samples revealed rimmed vacuoles stained positive for both ubiquitin and p97.[54] In patient brain tissues, neuronal nuclear inclusions were also detected and stained positive for ubiquitin and p97.[57] More recent studies found inclusions positive for TAR DNA-binding Protein-43 (TDP-43) in patient samples.[58] These findings suggest that defects in p97-regulated protein quality control network may contribute to the etiology the disease.

To date, 20 missense mutations in p97 have been reported in IBMPFD patients, involving amino acid changes at 14 different positions in p97.[59] In all cases, only single amino acid substitution was observed. Intriguingly, these mutations are all located at the interface between the N- and D1-domain (N-D1 interface). This observation suggests that communications between the N domain and the D1 domain may be critical for p97 function.

Autosomal dominantly inherited amyotrophic lateral sclerosis (ALS) is another disease genetically linked to mutations in p97. ALS is clinically characterized by dysfunction in motor neuron, resulting in progressive paralysis and death from respiratory failure. Unlike IBMPFD, ALS-associated p97 mutations are predominantly found in the D2 domain, which account for ~1%–2% of familial ALS cases.[55] The pathological hallmark of the disease, loss of motor neurons, is often associated with the presence of ubiquitin-positive inclusions or deposition of TDP-43 aggregates in motor neuron. This once again links the etiology of ALS to defects in quality control of misfolded proteins, but how mutations in p97 cause ALS is currently unclear.

Cancer therapy[edit]

The first p97 inhibitor Eeyarestatin (EerI) was discovered by screening and characterizing compounds that inhibit the degradation of a fluorescence-labeled ERAD substrate.[60][61] The mechanism of p97 inhibition by EerI is unclear, but when applied to cells, it induces biological phenotypes associated with p97 inhibition such as ERAD inhibition, ER stress elevation, and apoptosis induction. Importantly, EerI displays significant cancer-killing activity in vitro preferentially against cancer cells isolated from patients, and it can synergize with the proteasome inhibitor Bortezomib to kill cancer cells.[62] These observations prompt the idea of targeting p97 as a potential cancer therapy. This idea was further confirmed by studying several ATP competitive and allosteric inhibitors.[63][64][65] More recently, a potent and specific p97 inhibitor CB-5083 has been developed, which demonstrates promising anti-cancer activities in mouse xenograft tumor models.[66] The compound is now being evaluated in a phase 1 clinical trial.


  1. ^ Druck T, Gu Y, Prabhala G, Cannizzaro LA, Park SH, Huebner K, Keen JH (Nov 1995). "Chromosome localization of human genes for clathrin adaptor polypeptides AP2 beta and AP50 and the clathrin-binding protein, VCP". Genomics 30 (1): 94–7. doi:10.1006/geno.1995.0016. PMID 8595912. 
  2. ^ a b Rabouille C, Levine TP, Peters JM, Warren G (Sep 1995). "An NSF-like ATPase, p97, and NSF mediate cisternal regrowth from mitotic Golgi fragments". Cell 82 (6): 905–14. PMID 7553851. 
  3. ^ "Entrez Gene: VCP valosin-containing protein". 
  4. ^ Ogura T, Wilkinson AJ (Jul 2001). "AAA+ superfamily ATPases: common structure--diverse function". Genes to Cells 6 (7): 575–97. PMID 11473577. 
  5. ^ a b Ye Y (Oct 2006). "Diverse functions with a common regulator: ubiquitin takes command of an AAA ATPase". Journal of Structural Biology 156 (1): 29–40. doi:10.1016/j.jsb.2006.01.005. PMID 16529947. 
  6. ^ Moir D, Stewart SE, Osmond BC, Botstein D (Apr 1982). "Cold-sensitive cell-division-cycle mutants of yeast: isolation, properties, and pseudoreversion studies". Genetics 100 (4): 547–63. PMC 1201831. PMID 6749598. 
  7. ^ Koller KJ, Brownstein MJ (1987). "Use of a cDNA clone to identify a supposed precursor protein containing valosin". Nature 325 (6104): 542–5. Bibcode:1987Natur.325..542K. doi:10.1038/325542a0. PMID 3468358. 
  8. ^ Acharya U, Jacobs R, Peters JM, Watson N, Farquhar MG, Malhotra V (Sep 1995). "The formation of Golgi stacks from vesiculated Golgi membranes requires two distinct fusion events". Cell 82 (6): 895–904. PMID 7553850. 
  9. ^ Latterich M, Fröhlich KU, Schekman R (Sep 1995). "Membrane fusion and the cell cycle: Cdc48p participates in the fusion of ER membranes". Cell 82 (6): 885–93. PMID 7553849. 
  10. ^ a b Xu S, Peng G, Wang Y, Fang S, Karbowski M (Feb 2011). "The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover". Molecular Biology of the Cell 22 (3): 291–300. doi:10.1091/mbc.E10-09-0748. PMC 3031461. PMID 21118995. 
  11. ^ Ramanathan HN, Ye Y (Feb 2012). "The p97 ATPase associates with EEA1 to regulate the size of early endosomes". Cell Research 22 (2): 346–59. doi:10.1038/cr.2011.80. PMC 3271578. PMID 21556036. 
  12. ^ Madeo F, Schlauer J, Zischka H, Mecke D, Fröhlich KU (Jan 1998). "Tyrosine phosphorylation regulates cell cycle-dependent nuclear localization of Cdc48p". Molecular Biology of the Cell 9 (1): 131–41. PMC 25228. PMID 9436996. 
  13. ^ DeLaBarre B, Brunger AT (Oct 2003). "Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains". Nature Structural Biology 10 (10): 856–63. doi:10.1038/nsb972. PMID 12949490. 
  14. ^ Davies JM, Brunger AT, Weis WI (May 2008). "Improved structures of full-length p97, an AAA ATPase: implications for mechanisms of nucleotide-dependent conformational change". Structure 16 (5): 715–26. doi:10.1016/j.str.2008.02.010. PMID 18462676. 
  15. ^ Wang Q, Song C, Li CC (Jan 2003). "Hexamerization of p97-VCP is promoted by ATP binding to the D1 domain and required for ATPase and biological activities". Biochemical and Biophysical Research Communications 300 (2): 253–60. PMID 12504076. 
  16. ^ Beuron F, Dreveny I, Yuan X, Pye VE, McKeown C, Briggs LC, Cliff MJ, Kaneko Y, Wallis R, Isaacson RL, Ladbury JE, Matthews SJ, Kondo H, Zhang X, Freemont PS (May 2006). "Conformational changes in the AAA ATPase p97-p47 adaptor complex". The EMBO Journal 25 (9): 1967–76. doi:10.1038/sj.emboj.7601055. PMC 1456939. PMID 16601695. 
  17. ^ Beuron F, Flynn TC, Ma J, Kondo H, Zhang X, Freemont PS (Mar 2003). "Motions and negative cooperativity between p97 domains revealed by cryo-electron microscopy and quantised elastic deformational model". Journal of Molecular Biology 327 (3): 619–29. PMID 12634057. 
  18. ^ DeLaBarre B, Brunger AT (Mar 2005). "Nucleotide dependent motion and mechanism of action of p97/VCP". Journal of Molecular Biology 347 (2): 437–52. doi:10.1016/j.jmb.2005.01.060. PMID 15740751. 
  19. ^ Rouiller I, DeLaBarre B, May AP, Weis WI, Brunger AT, Milligan RA, Wilson-Kubalek EM (Dec 2002). "Conformational changes of the multifunction p97 AAA ATPase during its ATPase cycle". Nature Structural Biology 9 (12): 950–7. doi:10.1038/nsb872. PMID 12434150. 
  20. ^ Tang WK, Li D, Li CC, Esser L, Dai R, Guo L, Xia D (Jul 2010). "A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants". The EMBO Journal 29 (13): 2217–29. doi:10.1038/emboj.2010.104. PMC 2905243. PMID 20512113. 
  21. ^ Wang Q, Song C, Li CC (2004). "Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions". Journal of Structural Biology 146 (1–2): 44–57. doi:10.1016/j.jsb.2003.11.014. PMID 15037236. 
  22. ^ Nishikori S, Esaki M, Yamanaka K, Sugimoto S, Ogura T (May 2011). "Positive cooperativity of the p97 AAA ATPase is critical for essential functions". The Journal of Biological Chemistry 286 (18): 15815–20. doi:10.1074/jbc.M110.201400. PMC 3091191. PMID 21454554. 
  23. ^ a b Tang WK, Xia D (Dec 2013). "Altered intersubunit communication is the molecular basis for functional defects of pathogenic p97 mutants". The Journal of Biological Chemistry 288 (51): 36624–35. doi:10.1074/jbc.M113.488924. PMC 3868774. PMID 24196964. 
  24. ^ Ye Y, Meyer HH, Rapoport TA (Jul 2003). "Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains". The Journal of Cell Biology 162 (1): 71–84. doi:10.1083/jcb.200302169. PMC 2172719. PMID 12847084. 
  25. ^ a b Song C, Wang Q, Li CC (Feb 2003). "ATPase activity of p97-valosin-containing protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity". The Journal of Biological Chemistry 278 (6): 3648–55. doi:10.1074/jbc.M208422200. PMID 12446676. 
  26. ^ DeLaBarre B, Christianson JC, Kopito RR, Brunger AT (May 2006). "Central pore residues mediate the p97/VCP activity required for ERAD". Molecular Cell 22 (4): 451–62. doi:10.1016/j.molcel.2006.03.036. PMID 16713576. 
  27. ^ Meyer HH, Kondo H, Warren G (Oct 1998). "The p47 co-factor regulates the ATPase activity of the membrane fusion protein, p97". FEBS Letters 437 (3): 255–7. PMID 9824302. 
  28. ^ Zhang X, Gui L, Zhang X, Bulfer SL, Sanghez V, Wong DE, Lee Y, Lehmann L, Lee JS, Shih PY, Lin HJ, Iacovino M, Weihl CC, Arkin MR, Wang Y, Chou TF (Apr 2015). "Altered cofactor regulation with disease-associated p97/VCP mutations". Proceedings of the National Academy of Sciences of the United States of America 112 (14): E1705–14. Bibcode:2015PNAS..112E1705Z. doi:10.1073/pnas.1418820112. PMC 4394316. PMID 25775548. 
  29. ^ Halawani D, LeBlanc AC, Rouiller I, Michnick SW, Servant MJ, Latterich M (Aug 2009). "Hereditary inclusion body myopathy-linked p97/VCP mutations in the NH2 domain and the D1 ring modulate p97/VCP ATPase activity and D2 ring conformation". Molecular and Cellular Biology 29 (16): 4484–94. doi:10.1128/MCB.00252-09. PMC 2725746. PMID 19506019. 
  30. ^ Weihl CC, Dalal S, Pestronk A, Hanson PI (Jan 2006). "Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation". Human Molecular Genetics 15 (2): 189–99. doi:10.1093/hmg/ddi426. PMID 16321991. 
  31. ^ Ye Y, Meyer HH, Rapoport TA (Dec 2001). "The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol". Nature 414 (6864): 652–6. doi:10.1038/414652a. PMID 11740563. 
  32. ^ Kondo H, Rabouille C, Newman R, Levine TP, Pappin D, Freemont P, Warren G (Jul 1997). "p47 is a cofactor for p97-mediated membrane fusion". Nature 388 (6637): 75–8. doi:10.1038/40411. PMID 9214505. 
  33. ^ Song EJ, Yim SH, Kim E, Kim NS, Lee KJ (Mar 2005). "Human Fas-associated factor 1, interacting with ubiquitinated proteins and valosin-containing protein, is involved in the ubiquitin-proteasome pathway". Molecular and Cellular Biology 25 (6): 2511–24. doi:10.1128/MCB.25.6.2511-2524.2005. PMC 1061599. PMID 15743842. 
  34. ^ Qiu L, Pashkova N, Walker JR, Winistorfer S, Allali-Hassani A, Akutsu M, Piper R, Dhe-Paganon S (Jan 2010). "Structure and function of the PLAA/Ufd3-p97/Cdc48 complex". The Journal of Biological Chemistry 285 (1): 365–72. doi:10.1074/jbc.M109.044685. PMC 2804184. PMID 19887378. 
  35. ^ Zhao G, Zhou X, Wang L, Li G, Schindelin H, Lennarz WJ (May 2007). "Studies on peptide:N-glycanase-p97 interaction suggest that p97 phosphorylation modulates endoplasmic reticulum-associated degradation". Proceedings of the National Academy of Sciences of the United States of America 104 (21): 8785–90. Bibcode:2007PNAS..104.8785Z. doi:10.1073/pnas.0702966104. PMC 1885580. PMID 17496150. 
  36. ^ Schaeffer V, Akutsu M, Olma MH, Gomes LC, Kawasaki M, Dikic I (May 2014). "Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling". Molecular Cell 54 (3): 349–61. doi:10.1016/j.molcel.2014.03.016. PMID 24726327. 
  37. ^ Schuberth C, Buchberger A (Aug 2008). "UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97". Cellular and Molecular Life Sciences 65 (15): 2360–71. doi:10.1007/s00018-008-8072-8. PMID 18438607. 
  38. ^ Stapf C, Cartwright E, Bycroft M, Hofmann K, Buchberger A (Nov 2011). "The general definition of the p97/valosin-containing protein (VCP)-interacting motif (VIM) delineates a new family of p97 cofactors". The Journal of Biological Chemistry 286 (44): 38670–8. doi:10.1074/jbc.M111.274472. PMC 3207395. PMID 21896481. 
  39. ^ Ballar P, Shen Y, Yang H, Fang S (Nov 2006). "The role of a novel p97/valosin-containing protein-interacting motif of gp78 in endoplasmic reticulum-associated degradation". The Journal of Biological Chemistry 281 (46): 35359–68. doi:10.1074/jbc.M603355200. PMID 16987818. 
  40. ^ Ballar P, Zhong Y, Nagahama M, Tagaya M, Shen Y, Fang S (Nov 2007). "Identification of SVIP as an endogenous inhibitor of endoplasmic reticulum-associated degradation". The Journal of Biological Chemistry 282 (47): 33908–14. doi:10.1074/jbc.M704446200. PMID 17872946. 
  41. ^ Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA (Jun 2004). "A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol". Nature 429 (6994): 841–7. Bibcode:2004Natur.429..841Y. doi:10.1038/nature02656. PMID 15215856. 
  42. ^ Hänzelmann P, Schindelin H (Nov 2011). "The structural and functional basis of the p97/valosin-containing protein (VCP)-interacting motif (VIM): mutually exclusive binding of cofactors to the N-terminal domain of p97". The Journal of Biological Chemistry 286 (44): 38679–90. doi:10.1074/jbc.M111.274506. PMC 3207442. PMID 21914798. 
  43. ^ Meyer HH, Shorter JG, Seemann J, Pappin D, Warren G (May 2000). "A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways". The EMBO Journal 19 (10): 2181–92. doi:10.1093/emboj/19.10.2181. PMC 384367. PMID 10811609. 
  44. ^ Buchberger A, Schindelin H, Hänzelmann P (Sep 2015). "Control of p97 function by cofactor binding". FEBS Letters 589 (19 Pt A): 2578–89. doi:10.1016/j.febslet.2015.08.028. PMID 26320413. 
  45. ^ Meyer H, Bug M, Bremer S (Feb 2012). "Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system". Nature Cell Biology 14 (2): 117–23. doi:10.1038/ncb2407. PMID 22298039. 
  46. ^ Christianson JC, Ye Y (Apr 2014). "Cleaning up in the endoplasmic reticulum: ubiquitin in charge". Nature Structural & Molecular Biology 21 (4): 325–35. doi:10.1038/nsmb.2793. PMID 24699081. 
  47. ^ Brandman O, Stewart-Ornstein J, Wong D, Larson A, Williams CC, Li GW, Zhou S, King D, Shen PS, Weibezahn J, Dunn JG, Rouskin S, Inada T, Frost A, Weissman JS (Nov 2012). "A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress". Cell 151 (5): 1042–54. doi:10.1016/j.cell.2012.10.044. PMC 3534965. PMID 23178123. 
  48. ^ Defenouillère Q, Yao Y, Mouaikel J, Namane A, Galopier A, Decourty L, Doyen A, Malabat C, Saveanu C, Jacquier A, Fromont-Racine M (Mar 2013). "Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products". Proceedings of the National Academy of Sciences of the United States of America 110 (13): 5046–51. doi:10.1073/pnas.1221724110. PMC 3612664. PMID 23479637. 
  49. ^ Verma R, Oania RS, Kolawa NJ, Deshaies RJ (2013). "Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome". ELife 2: e00308. doi:10.7554/eLife.00308. PMC 3552423. PMID 23358411. 
  50. ^ Gallagher PS, Clowes Candadai SV, Gardner RG (May 2014). "The requirement for Cdc48/p97 in nuclear protein quality control degradation depends on the substrate and correlates with substrate insolubility". Journal of Cell Science 127 (Pt 9): 1980–91. doi:10.1242/jcs.141838. PMC 4004975. PMID 24569878. 
  51. ^ a b Bug M, Meyer H (Aug 2012). "Expanding into new markets--VCP/p97 in endocytosis and autophagy". Journal of Structural Biology 179 (2): 78–82. doi:10.1016/j.jsb.2012.03.003. PMID 22450227. 
  52. ^ Dantuma NP, Acs K, Luijsterburg MS (Nov 2014). "Should I stay or should I go: VCP/p97-mediated chromatin extraction in the DNA damage response". Experimental Cell Research 329 (1): 9–17. doi:10.1016/j.yexcr.2014.08.025. PMID 25169698. 
  53. ^ Uchiyama K, Kondo H (Feb 2005). "p97/p47-Mediated biogenesis of Golgi and ER". Journal of Biochemistry 137 (2): 115–9. doi:10.1093/jb/mvi028. PMID 15749824. 
  54. ^ a b Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE (Apr 2004). "Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein". Nature Genetics 36 (4): 377–81. doi:10.1038/ng1332. PMID 15034582. 
  55. ^ a b Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, Ding J, McCluskey L, Martinez-Lage M, Falcone D, Hernandez DG, Arepalli S, Chong S, Schymick JC, Rothstein J, Landi F, Wang YD, Calvo A, Mora G, Sabatelli M, Monsurrò MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Galassi G, Scholz SW, Taylor JP, Restagno G, Chiò A, Traynor BJ (Dec 2010). "Exome sequencing reveals VCP mutations as a cause of familial ALS". Neuron 68 (5): 857–64. doi:10.1016/j.neuron.2010.11.036. PMC 3032425. PMID 21145000. 
  56. ^ Kimonis VE, Kovach MJ, Waggoner B, Leal S, Salam A, Rimer L, Davis K, Khardori R, Gelber D (2000). "Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone". Genetics in Medicine 2 (4): 232–41. doi:10.1097/00125817-200001000-00103. PMID 11252708. 
  57. ^ Kimonis VE, Watts GD (2005). "Autosomal dominant inclusion body myopathy, Paget disease of bone, and frontotemporal dementia". Alzheimer Disease and Associated Disorders. 19 Suppl 1: S44–7. PMID 16317258. 
  58. ^ Weihl CC, Temiz P, Miller SE, Watts G, Smith C, Forman M, Hanson PI, Kimonis V, Pestronk A (Oct 2008). "TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia". Journal of Neurology, Neurosurgery, and Psychiatry 79 (10): 1186–9. doi:10.1136/jnnp.2007.131334. PMC 2586594. PMID 18796596. 
  59. ^ Nalbandian A, Donkervoort S, Dec E, Badadani M, Katheria V, Rana P, Nguyen C, Mukherjee J, Caiozzo V, Martin B, Watts GD, Vesa J, Smith C, Kimonis VE (Nov 2011). "The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis". Journal of Molecular Neuroscience 45 (3): 522–31. doi:10.1007/s12031-011-9627-y. PMID 21892620. 
  60. ^ Fiebiger E, Hirsch C, Vyas JM, Gordon E, Ploegh HL, Tortorella D (Apr 2004). "Dissection of the dislocation pathway for type I membrane proteins with a new small molecule inhibitor, eeyarestatin". Molecular Biology of the Cell 15 (4): 1635–46. doi:10.1091/mbc.E03-07-0506. PMC 379262. PMID 14767067. 
  61. ^ Wang Q, Shinkre BA, Lee JG, Weniger MA, Liu Y, Chen W, Wiestner A, Trenkle WC, Ye Y (2010). "The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group". PloS One 5 (11): e15479. Bibcode:2010PLoSO...515479W. doi:10.1371/journal.pone.0015479. PMC 2993181. PMID 21124757. 
  62. ^ Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y (Feb 2009). "ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells". Proceedings of the National Academy of Sciences of the United States of America 106 (7): 2200–5. Bibcode:2009PNAS..106.2200W. doi:10.1073/pnas.0807611106. PMC 2629785. PMID 19164757. 
  63. ^ Chou TF, Li K, Frankowski KJ, Schoenen FJ, Deshaies RJ (Feb 2013). "Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase". ChemMedChem 8 (2): 297–312. doi:10.1002/cmdc.201200520. PMC 3662613. PMID 23316025. 
  64. ^ Chou TF, Brown SJ, Minond D, Nordin BE, Li K, Jones AC, Chase P, Porubsky PR, Stoltz BM, Schoenen FJ, Patricelli MP, Hodder P, Rosen H, Deshaies RJ (Mar 2011). "Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways". Proceedings of the National Academy of Sciences of the United States of America 108 (12): 4834–9. Bibcode:2011PNAS..108.4834C. doi:10.1073/pnas.1015312108. PMC 3064330. PMID 21383145. 
  65. ^ Magnaghi P, D'Alessio R, Valsasina B, Avanzi N, Rizzi S, Asa D, Gasparri F, Cozzi L, Cucchi U, Orrenius C, Polucci P, Ballinari D, Perrera C, Leone A, Cervi G, Casale E, Xiao Y, Wong C, Anderson DJ, Galvani A, Donati D, O'Brien T, Jackson PK, Isacchi A (Sep 2013). "Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death". Nature Chemical Biology 9 (9): 548–56. doi:10.1038/nchembio.1313. PMID 23892893. 
  66. ^ Anderson DJ, Le Moigne R, Djakovic S, Kumar B, Rice J, Wong S, Wang J, Yao B, Valle E, Kiss von Soly S, Madriaga A, Soriano F, Menon MK, Wu ZY, Kampmann M, Chen Y, Weissman JS, Aftab BT, Yakes FM, Shawver L, Zhou HJ, Wustrow D, Rolfe M (Nov 2015). "Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis". Cancer Cell 28 (5): 653–65. doi:10.1016/j.ccell.2015.10.002. PMID 26555175. 

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