Valosin-containing protein

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 affect cell growth at non-permissive temperatures. A search for the mammalian homolog of CDC48 (valosin) revealed a 97 kDa protein precursor named "valosin-containing protein (VCP)" or p97, and also showed that it was only generated as an artefact of purification rather than during physiological processing. Even without evidence that valosin is a physiological product, the VCP nomenclature continues to be used in the literature.

VCP 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 VCP was found to be moderately elevated in certain types of cancer.

In mammalian cells, VCP 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 VCP was also found in the nucleus.

According to the crystal structures of full-length wild-type VCP, six VCP subunits assemble into a barrel-like structure, in which the N-D1 and D2 domains form two concentric, stacked rings (Figure 2). File:VCP Wiki Figure 2.jpg 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 VCP only requires the D1 but not the D2 domain. Unlike many bacterial AAA+ proteins, assembly of VCP hexamer does not depend on the presence of nucleotide. The VCP 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 VCP generates force is unclear.

The ATP hydrolyzing activity is indispensable for the VCP functions. The two ATPase domains of VCP (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. 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 VCP can be influenced by many factors. For example, it can be stimulated by heat or by a putative substrate protein. In Leishmania infantum, the LiVCP protein is essential for the intracellular development of the parasite and its survival under heat stress.{{cite journal | vauthors = Guedes Aguiar B, Padmanabhan PK, Dumas C, Papadopoulou B | title = Valosin-containing protein VCP/p97 is essential for the intracellular development of Leishmania and its survival under heat stress | journal = Cellular Microbiology | volume = 20 | issue = 10 | pages = e12867 | date = June 2018 | pmid = 29895095 | doi = 10.1111/cmi.12867 | s2cid = 48359590 | doi-access = free }} Association with cofactors can have either positive or negative impact on the p97 ATPase activity.

Mutations in VCP can also influence its activity. For example, VCP mutant proteins carrying single point mutations found in patients with multisystem proteinopathy (MSP; formerly known as IBMPFD (inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia)) (see below) have 2-3 fold increase in ATPase activity.

Recent proteomic studies have identified a large number of p97-interacting proteins. Many of these proteins serve as adaptors that link VCP to a particular subcellular compartment to function in a specific cellular

pathway. Others function as adaptors that recruit substrates to VCP for processing. Some VCP-interacting proteins are also enzymes such as N-glycanase, ubiquitin ligase, and deubiquitinase, which assist VCP in processing substrates.

Most cofactors bind VCP through its N-domain, but a few interact with the short carboxy-terminal tail in VCP. Representative proteins interacting with the N-domain are Ufd1, Npl4, p47 and FAF1. Examples of cofactors that interact with the carboxy-terminal tail of VCP are PLAA, PNGase, and Ufd2.

The molecular basis for cofactor binding has been studied for some cofactors that interact with the VCP 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). File:VCP Wiki Figure 3.jpg 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 VCP, two most frequently occurring sequence motifs are found: one is called UBX motif (ubiquitin regulatory X) and the other is termed VIM (VCP-interacting motif). The UBX domain is an 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 VCP cofactors including gp78, SVIP (small VCP-interacting protein) and VIMP (VCP interacting membrane protein). Although the UBX domain uses a surface loop whereas the VIM forms a-helix to bind VCP, both UBX and VIM bind at the same location between the two sub-domains of the N-domain (Figure 3). It was proposed that hierarchical binding to distinct cofactors may be essential for the broad functions of VCP.

VCP performs diverse functions through modulating the stability and thus the activity of its substrates. The general function of VCP 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 VCP can be grouped into the following three major categories.

The best characterized function of VCP is to mediate a network of protein quality control processes in order to maintain protein homeostasis. These include endoplasmic reticulum-associated protein degradation (ERAD) and mitochondria-associated degradation. In these processes, ATP hydrolysis by VCP is required to extract aberrant proteins from the membranes of the ER or mitochondria. VCP is also required to release defective translation products stalled on ribosome in a process termed ribosome-associated degradation. 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, VCP 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. 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 VCP in this process is unclear.

VCP also functions broadly in eukaryotic nucleus by releasing protein molecules from chromatins in a manner analogous to that in ERAD. The identified VCP 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 VCP function to gene transcription, DNA replication and repair, and cell cycle progression.

Biochemical and genetic studies have also implicated VCP in fusion of vesicles that lead to the formation of Golgi apparatus at the end of mitosis. 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 VCP in Golgi formation is unclear due to lack of information on relevant substrate(s). Recent studies also suggest that VCP may regulate vesicle trafficking from plasma membrane to the lysosome, a process termed endocytosis. Antibody fragment-based inhibitors have been developed by a team led by Arkin to inhibit the interaction between p97 and p47, selectively modulating the Golgi reassembly process.{{Cite journal |last1=Jiang |first1=Ziwen |last2=Kuo |first2=Yu-Hsuan |last3=Zhong |first3=Mengqi |last4=Zhang |first4=Jianchao |last5=Zhou |first5=Xin X. |last6=Xing |first6=Lijuan |last7=Wells |first7=James A. |last8=Wang |first8=Yanzhuang |last9=Arkin |first9=Michelle R. |date=2022-07-27 |title=Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein–Protein Interactions |journal=Journal of the American Chemical Society |language=en |volume=144 |issue=29 |pages=13218–13225 |doi=10.1021/jacs.2c03665 |issn=0002-7863 |pmc=9335864 |pmid=35819848}}

Mutations in VCP were first reported to cause a syndrome characterized by frontotemporal dementia, inclusion body myopathy, and Paget's disease of the bone by Virginia Kimonis in 2004.{{Cite journal|last1=Watts|first1=Giles D. J.|last2=Wymer|first2=Jill|last3=Kovach|first3=Margaret J.|last4=Mehta|first4=Sarju G.|last5=Mumm|first5=Steven|last6=Darvish|first6=Daniel|last7=Pestronk|first7=Alan|last8=Whyte|first8=Michael P.|last9=Kimonis|first9=Virginia E.|date=2004|title=Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein|journal=Nature Genetics|volume=36|issue=4|pages=377–381|doi=10.1038/ng1332|issn=1061-4036|pmid=15034582|doi-access=free}} In 2010, mutations in VCP were also found to be a cause of amyotrophic lateral sclerosis by Bryan Traynor and Adriano Chiò.{{Cite journal|last1=Johnson|first1=Janel O.|last2=Mandrioli|first2=Jessica|last3=Benatar|first3=Michael|last4=Abramzon|first4=Yevgeniya|last5=Van Deerlin|first5=Vivianna M.|last6=Trojanowski|first6=John Q.|last7=Gibbs|first7=J. Raphael|last8=Brunetti|first8=Maura|last9=Gronka|first9=Susan|date=2010-12-09|title=Exome sequencing reveals VCP mutations as a cause of familial ALS|journal=Neuron|volume=68|issue=5|pages=857–864|doi=10.1016/j.neuron.2010.11.036|issn=1097-4199|pmc=3032425|pmid=21145000}} This discovery was notable as it represented an initial genetic link between two disparate neurological diseases, amyotrophic lateral sclerosis and frontotemporal dementia. In 2020, Edward Lee described a distinct hypomorphic mutation in VCP associated with vacuolar tauopathy, a unique subtype of frontotemporal lobar degeneration with tau inclusions.{{cite journal | author = Darwich, N.F., Phan J.M.| display-authors = etal | title = Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau | journal = Science | year = 2020 | volume = 370 | issue= 6519 | pages= eaay8826 | doi=10.1126/science.aay8826 | pmid= 33004675| pmc=7818661}}

Mutations in VCP are an example of pleiotropy, where mutations in the same gene give rise to different phenotypes. The term multisystem proteinopathy (MSP) has been coined to describe this particular form of pleiotropy.{{Cite journal|last=Taylor|first=J. Paul|date=2015-08-25|title=Multisystem proteinopathy: intersecting genetics in muscle, bone, and brain degeneration|journal=Neurology|volume=85|issue=8|pages=658–660|doi=10.1212/WNL.0000000000001862|issn=1526-632X|pmid=26208960|s2cid=42203997}} Although MSP is rare, growing interest in this syndrome derives from the molecular insights the condition provides into the etiological relationship between common age-related degenerative diseases of muscle, bone and brain. It has been estimated that ~50% of MSP may be caused by missense mutations affecting the valosin-containing protein (VCP) gene.{{cite journal | vauthors = Le Ber I, Van Bortel I, Nicolas G, Bouya-Ahmed K, Camuzat A, Wallon D, De Septenville A, Latouche M, Lattante S, Kabashi E, Jornea L, Hannequin D, Brice A | title = hnRNPA2B1 and hnRNPA1 mutations are rare in patients with "multisystem proteinopathy" and frontotemporal lobar degeneration phenotypes | journal = Neurobiology of Aging | volume = 35 | issue = 4 | pages = 934.e5–6 | date = April 2014 | pmid = 24119545 | doi = 10.1016/j.neurobiolaging.2013.09.016 | s2cid = 207160856 }}

The first p97 inhibitor Eeyarestatin (EerI) was discovered by screening and characterizing compounds that inhibit the degradation of a fluorescence-labeled ERAD substrate. The mechanism of VCP inhibition by EerI is unclear, but when applied to cells, it induces biological phenotypes associated with VCP 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. These observations prompt the idea of targeting VCP as a potential cancer therapy. This idea was further confirmed by studying several ATP competitive and allosteric inhibitors. More recently, a potent and specific VCP inhibitor CB-5083 has been developed, which demonstrates promising anti-cancer activities in mouse xenograft tumor models. The compound is now being evaluated in a phase 1 clinical trial.{{cite journal | vauthors = Zhou HJ, Wang J, Yao B, Wong S, Djakovic S, Kumar B, Rice J, Valle E, Soriano F, Menon MK, Madriaga A, Kiss von Soly S, Kumar A, Parlati F, Yakes FM, Shawver L, Le Moigne R, Anderson DJ, Rolfe M, Wustrow D | title = Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the VCP AAA ATPase (CB-5083) | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 24 | pages = 9480–97 | date = December 2015 | pmid = 26565666 | doi = 10.1021/acs.jmedchem.5b01346 | doi-access = free }}

{{Academic-written review|Q=Q36767612}}

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40 {{cite journal | vauthors = Hänzelmann P, Schindelin H | title = 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 | journal = The Journal of Biological Chemistry | volume = 286 | issue = 44 | pages = 38679–90 | date = November 2011 | pmid = 21914798 | pmc = 3207442 | doi = 10.1074/jbc.M111.274506 | doi-access = free }}

41 {{cite journal | vauthors = Meyer HH, Shorter JG, Seemann J, Pappin D, Warren G | title = A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways | journal = The EMBO Journal | volume = 19 | issue = 10 | pages = 2181–92 | date = May 2000 | pmid = 10811609 | pmc = 384367 | doi = 10.1093/emboj/19.10.2181 }}

42 {{cite journal | vauthors = Buchberger A, Schindelin H, Hänzelmann P | title = Control of p97 function by cofactor binding | journal = FEBS Letters | volume = 589 | issue = 19 Pt A | pages = 2578–89 | date = September 2015 | pmid = 26320413 | doi = 10.1016/j.febslet.2015.08.028 | s2cid = 41082524 | doi-access = free }}

43 {{cite journal | vauthors = Meyer H, Bug M, Bremer S | title = Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system | journal = Nature Cell Biology | volume = 14 | issue = 2 | pages = 117–23 | date = February 2012 | pmid = 22298039 | doi = 10.1038/ncb2407 | s2cid = 23562362 }}

44 {{cite journal | vauthors = Christianson JC, Ye Y | title = Cleaning up in the endoplasmic reticulum: ubiquitin in charge | journal = Nature Structural & Molecular Biology | volume = 21 | issue = 4 | pages = 325–35 | date = April 2014 | pmid = 24699081 | doi = 10.1038/nsmb.2793 | pmc = 9397582 | s2cid = 43665193 }}

45 {{cite journal | vauthors = 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 | title = A ribosome-bound quality control complex triggers degradation of nascent peptides and signals translation stress | journal = Cell | volume = 151 | issue = 5 | pages = 1042–54 | date = November 2012 | pmid = 23178123 | pmc = 3534965 | doi = 10.1016/j.cell.2012.10.044 }}

46 {{cite journal | vauthors = Defenouillère Q, Yao Y, Mouaikel J, Namane A, Galopier A, Decourty L, Doyen A, Malabat C, Saveanu C, Jacquier A, Fromont-Racine M | title = Cdc48-associated complex bound to 60S particles is required for the clearance of aberrant translation products | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 13 | pages = 5046–51 | date = March 2013 | pmid = 23479637 | pmc = 3612664 | doi = 10.1073/pnas.1221724110 | bibcode = 2013PNAS..110.5046D | doi-access = free }}

47 {{cite journal | vauthors = Verma R, Oania RS, Kolawa NJ, Deshaies RJ | title = Cdc48/p97 promotes degradation of aberrant nascent polypeptides bound to the ribosome | journal = eLife | volume = 2 | pages = e00308 | date = January 2013 | pmid = 23358411 | pmc = 3552423 | doi = 10.7554/eLife.00308 | doi-access = free }}

48 {{cite journal | vauthors = Gallagher PS, Clowes Candadai SV, Gardner RG | title = The requirement for Cdc48/p97 in nuclear protein quality control degradation depends on the substrate and correlates with substrate insolubility | journal = Journal of Cell Science | volume = 127 | issue = Pt 9 | pages = 1980–91 | date = May 2014 | pmid = 24569878 | pmc = 4004975 | doi = 10.1242/jcs.141838 }}

49 {{cite journal | vauthors = Bug M, Meyer H | title = Expanding into new markets--VCP/p97 in endocytosis and autophagy | journal = Journal of Structural Biology | volume = 179 | issue = 2 | pages = 78–82 | date = August 2012 | pmid = 22450227 | doi = 10.1016/j.jsb.2012.03.003 }}

50 {{cite journal | vauthors = Dantuma NP, Acs K, Luijsterburg MS | title = Should I stay or should I go: VCP/p97-mediated chromatin extraction in the DNA damage response | journal = Experimental Cell Research | volume = 329 | issue = 1 | pages = 9–17 | date = November 2014 | pmid = 25169698 | doi = 10.1016/j.yexcr.2014.08.025 }}

51 {{cite journal | vauthors = Uchiyama K, Kondo H | title = p97/p47-Mediated biogenesis of Golgi and ER | journal = Journal of Biochemistry | volume = 137 | issue = 2 | pages = 115–9 | date = February 2005 | pmid = 15749824 | doi = 10.1093/jb/mvi028 | s2cid = 10459261 }}

52 {{cite journal | vauthors = Fiebiger E, Hirsch C, Vyas JM, Gordon E, Ploegh HL, Tortorella D | title = Dissection of the dislocation pathway for type I membrane proteins with a new small molecule inhibitor, eeyarestatin | journal = Molecular Biology of the Cell | volume = 15 | issue = 4 | pages = 1635–46 | date = April 2004 | pmid = 14767067 | pmc = 379262 | doi = 10.1091/mbc.E03-07-0506 }}

53 {{cite journal | vauthors = Wang Q, Shinkre BA, Lee JG, Weniger MA, Liu Y, Chen W, Wiestner A, Trenkle WC, Ye Y | title = The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group | journal = PLOS ONE | volume = 5 | issue = 11 | pages = e15479 | date = November 2010 | pmid = 21124757 | pmc = 2993181 | doi = 10.1371/journal.pone.0015479 | bibcode = 2010PLoSO...515479W | doi-access = free }}

54 {{cite journal | vauthors = Wang Q, Mora-Jensen H, Weniger MA, Perez-Galan P, Wolford C, Hai T, Ron D, Chen W, Trenkle W, Wiestner A, Ye Y | title = ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 7 | pages = 2200–5 | date = February 2009 | pmid = 19164757 | pmc = 2629785 | doi = 10.1073/pnas.0807611106 | bibcode = 2009PNAS..106.2200W | doi-access = free }}

55 {{cite journal | vauthors = Chou TF, Li K, Frankowski KJ, Schoenen FJ, Deshaies RJ | title = Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase | journal = ChemMedChem | volume = 8 | issue = 2 | pages = 297–312 | date = February 2013 | pmid = 23316025 | pmc = 3662613 | doi = 10.1002/cmdc.201200520 }}

56 {{cite journal | vauthors = 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 | title = Reversible inhibitor of p97, DBeQ, impairs both ubiquitin-dependent and autophagic protein clearance pathways | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 12 | pages = 4834–9 | date = March 2011 | pmid = 21383145 | pmc = 3064330 | doi = 10.1073/pnas.1015312108 | bibcode = 2011PNAS..108.4834C | doi-access = free }}

57 {{cite journal | vauthors = 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 | title = Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death | journal = Nature Chemical Biology | volume = 9 | issue = 9 | pages = 548–56 | date = September 2013 | pmid = 23892893 | doi = 10.1038/nchembio.1313 }}

58 {{cite journal | vauthors = 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 | title = Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis | journal = Cancer Cell | volume = 28 | issue = 5 | pages = 653–665 | date = November 2015 | pmid = 26555175 | pmc = 4941640 | doi = 10.1016/j.ccell.2015.10.002 }}

}}

{{refbegin|33em}}

• {{cite journal | vauthors = Guinto JB, Ritson GP, Taylor JP, Forman MS | title = Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy | journal = Acta Neuropathologica | volume = 114 | issue = 1 | pages = 55–61 | date = July 2007 | pmid = 17457594 | doi = 10.1007/s00401-007-0224-7 | s2cid = 2094590 }}
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• {{cite journal | vauthors = Pleasure IT, Black MM, Keen JH | title = Valosin-containing protein, VCP, is a ubiquitous clathrin-binding protein | journal = Nature | volume = 365 | issue = 6445 | pages = 459–62 | date = September 1993 | pmid = 8413590 | doi = 10.1038/365459a0 | bibcode = 1993Natur.365..459P | s2cid = 4307576 }}
• {{cite journal | vauthors = Germain-Lee EL, Obie C, Valle D | title = NVL: a new member of the AAA family of ATPases localized to the nucleus | journal = Genomics | volume = 44 | issue = 1 | pages = 22–34 | date = August 1997 | pmid = 9286697 | doi = 10.1006/geno.1997.4856 | doi-access = free }}
• {{cite journal | vauthors = Hoyle J, Tan KH, Fisher EM | title = Mapping the valosin-containing protein (VCP) gene on human chromosome 9 and mouse chromosome 4, and a likely pseudogene on the mouse X chromosome | journal = Mammalian Genome | volume = 8 | issue = 10 | pages = 778–80 | date = October 1997 | pmid = 9321476 | doi = 10.1007/s003359900566 | s2cid = 563437 }}
• {{cite journal | vauthors = Dai RM, Chen E, Longo DL, Gorbea CM, Li CC | title = Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome, in ubiquitin-proteasome-mediated degradation of IkappaBalpha | journal = The Journal of Biological Chemistry | volume = 273 | issue = 6 | pages = 3562–73 | date = February 1998 | pmid = 9452483 | doi = 10.1074/jbc.273.6.3562 | doi-access = free }}
• {{cite journal | vauthors = Rabouille C, Kondo H, Newman R, Hui N, Freemont P, Warren G | title = Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro | journal = Cell | volume = 92 | issue = 5 | pages = 603–10 | date = March 1998 | pmid = 9506515 | doi = 10.1016/S0092-8674(00)81128-9 | s2cid = 17285800 | doi-access = free }}
• {{cite journal | vauthors = Zhang SH, Liu J, Kobayashi R, Tonks NK | title = Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 25 | pages = 17806–12 | date = June 1999 | pmid = 10364224 | doi = 10.1074/jbc.274.25.17806 | doi-access = free }}
• {{cite journal | vauthors = Zhang H, Wang Q, Kajino K, Greene MI | title = VCP, a weak ATPase involved in multiple cellular events, interacts physically with BRCA1 in the nucleus of living cells | journal = DNA and Cell Biology | volume = 19 | issue = 5 | pages = 253–63 | date = May 2000 | pmid = 10855792 | doi = 10.1089/10445490050021168 }}
• {{cite journal | vauthors = Lavoie C, Chevet E, Roy L, Tonks NK, Fazel A, Posner BI, Paiement J, Bergeron JJ | title = Tyrosine phosphorylation of p97 regulates transitional endoplasmic reticulum assembly in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 25 | pages = 13637–42 | date = December 2000 | pmid = 11087817 | pmc = 17628 | doi = 10.1073/pnas.240278097 | bibcode = 2000PNAS...9713637L | doi-access = free }}
• {{cite journal | vauthors = Seigneurin-Berny D, Verdel A, Curtet S, Lemercier C, Garin J, Rousseaux S, Khochbin S | title = Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways | journal = Molecular and Cellular Biology | volume = 21 | issue = 23 | pages = 8035–44 | date = December 2001 | pmid = 11689694 | pmc = 99970 | doi = 10.1128/MCB.21.23.8035-8044.2001 }}
• {{cite journal | vauthors = Yang CS, Weiner H | title = Yeast two-hybrid screening identifies binding partners of human Tom34 that have ATPase activity and form a complex with Tom34 in the cytosol | journal = Archives of Biochemistry and Biophysics | volume = 400 | issue = 1 | pages = 105–10 | date = April 2002 | pmid = 11913976 | doi = 10.1006/abbi.2002.2778 }}
• {{cite journal | vauthors = Asai T, Tomita Y, Nakatsuka S, Hoshida Y, Myoui A, Yoshikawa H, Aozasa K | title = VCP (p97) regulates NFkappaB signaling pathway, which is important for metastasis of osteosarcoma cell line | journal = Japanese Journal of Cancer Research | volume = 93 | issue = 3 | pages = 296–304 | date = March 2002 | pmid = 11927012 | pmc = 5926968 | doi = 10.1111/j.1349-7006.2002.tb02172.x }}
• {{cite journal | vauthors = Kobayashi T, Tanaka K, Inoue K, Kakizuka A | title = Functional ATPase activity of p97/valosin-containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 49 | pages = 47358–65 | date = December 2002 | pmid = 12351637 | doi = 10.1074/jbc.M207783200 | doi-access = free }}
• {{cite journal | vauthors = Uchiyama K, Jokitalo E, Kano F, Murata M, Zhang X, Canas B, Newman R, Rabouille C, Pappin D, Freemont P, Kondo H | title = VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo | journal = The Journal of Cell Biology | volume = 159 | issue = 5 | pages = 855–66 | date = December 2002 | pmid = 12473691 | pmc = 2173386 | doi = 10.1083/jcb.200208112 }}

{{refend}}

• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ibmpfd GeneReviews/NIH/NCBI/UW entry on Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia]
• {{PDBe-KB2|P55072|Transitional endoplasmic reticulum ATPase}}

{{PDB Gallery|geneid=7415}}