Valosin-containing protein

"P97" redirects here. For other uses, see P97 (disambiguation).

VCP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 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, 5DYG
Identifiers
Aliases	VCP , ALS14, HEL-220, HEL-S-70, IBMPFD, IBMPFD1, TERA, p97, Valosin-containing protein, CMT2Y, valosin containing protein, CDC48, FTDALS6
External IDs	OMIM: 601023 MGI: 99919 HomoloGene: 5168 GeneCards: VCP
Gene location (Human) Chr. Chromosome 9 (human) [1] Band 9p13.3 Start 35,053,928 bp [1] End 35,072,668 bp [1]
Gene location (Mouse) Chr. Chromosome 4 (mouse) [2] Band 4 A5|4 22.95 cM Start 42,979,963 bp [2] End 43,000,507 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium islet of Langerhans gastrocnemius muscle right adrenal gland left adrenal gland minor salivary gland smooth muscle tissue anterior pituitary upper lobe of left lung left ventricle Top expressed in lip yolk sac superior frontal gyrus morula cerebellar cortex duodenum ganglionic eminence thymus spermatocyte proximal tubule More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding protein domain specific binding protein-containing complex binding ADP binding K48-linked polyubiquitin modification-dependent protein binding polyubiquitin modification-dependent protein binding protein binding ubiquitin-like protein ligase binding ubiquitin-specific protease binding MHC class I protein binding protein phosphatase binding deubiquitinase activator activity signaling receptor binding hydrolase activity ATP binding ubiquitin protein ligase binding lipid binding identical protein binding ATPase activity RNA binding BAT3 complex binding Cellular component site of double-strand break cytosol intracellular membrane-bounded organelle myelin sheath lipid droplet nucleoplasm VCP-NSFL1C complex endoplasmic reticulum Derlin-1 retrotranslocation complex VCP-NPL4-UFD1 AAA ATPase complex perinuclear region of cytoplasm proteasome complex nucleus extracellular exosome extracellular region secretory granule lumen azurophil granule lumen ficolin-1-rich granule lumen ATPase complex endoplasmic reticulum membrane cytoplasm cytoplasmic stress granule protein-containing complex synapse glutamatergic synapse Biological process regulation of aerobic respiration regulation of apoptotic process positive regulation of protein catabolic process positive regulation of protein-containing complex assembly ubiquitin-dependent protein catabolic process positive regulation of Lys63-specific deubiquitinase activity establishment of protein localization error-free translesion synthesis viral genome replication positive regulation of oxidative phosphorylation ER-associated misfolded protein catabolic process protein N-linked glycosylation via asparagine cellular response to DNA damage stimulus positive regulation of ATP biosynthetic process endoplasmic reticulum to Golgi vesicle-mediated transport ATP metabolic process retrograde protein transport, ER to cytosol NADH metabolic process positive regulation of protein K63-linked deubiquitination double-strand break repair ubiquitin-dependent ERAD pathway positive regulation of mitochondrial membrane potential activation of cysteine-type endopeptidase activity involved in apoptotic process protein homooligomerization positive regulation of proteasomal ubiquitin-dependent protein catabolic process protein hexamerization aggresome assembly flavin adenine dinucleotide catabolic process proteasome-mediated ubiquitin-dependent protein catabolic process autophagy DNA repair ERAD pathway positive regulation of ubiquitin-specific protease activity autophagosome maturation translesion synthesis protein folding protein methylation protein deubiquitination neutrophil degranulation transmembrane transport proteasomal protein catabolic process protein ubiquitination endoplasmic reticulum unfolded protein response endoplasmic reticulum stress-induced pre-emptive quality control macroautophagy endosome to lysosome transport via multivesicular body sorting pathway transport cellular response to heat stress granule disassembly regulation of synapse organization mitotic spindle disassembly positive regulation of canonical Wnt signaling pathway cellular response to arsenite ion Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7415 269523 Ensembl ENSG00000165280 ENSMUSG00000028452 UniProt P55072 Q01853 RefSeq (mRNA) NM_007126 NM_001354927 NM_001354928 NM_009503 RefSeq (protein) NP_009057 NP_001341856 NP_001341857 NP_033529 Location (UCSC) Chr 9: 35.05 – 35.07 Mb Chr 4: 42.98 – 43 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase (TER ATPase) also known as p97 in mammals and CDC48 in S. cerevisiae, is an enzyme that in humans is encoded by the VCP gene. ^{[5] [6] [7]} 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.

VCP/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. VCP is a type II AAA+ ATPase, which means that it contains two tandem ATPase domains (named D1 and D2, respectively) (Figure 1).

Figure 1- A schematic diagram of the p97 domain structure.

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. ^[8] The N-domain is connected to the D1 domain by a short N-D1 linker.

Most known substrates of VCP are modified with ubiquitin chains and degraded by the 26S proteasome. Accordingly, many VCP coenzymes and adaptors have domains that can recognize ubiquitin. ^[9] It has become evident that the interplays between ubiquitin and VCP cofactors are critical for many of the proposed functions, although the precise role of these interactions remains to be elucidated.

Discovery

CDC48 was discovered in a genetic screen for genes involved in cell cycle regulation in budding yeast. ^[10] 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. ^[11] Even without evidence that valosin is a physiological product, the VCP nomenclature continues to be used in the literature.

Tissue and subcelluar distribution

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. ^[9]

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. ^{[6] [12] [13] [14] [15]} 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. ^[16]

Structure

According to the crystal structures of full-length wild-type VCP, ^{[17] [18]} six VCP subunits assemble into a barrel-like structure, in which the N-D1 and D2 domains form two concentric, stacked rings (Figure2).

Figure 2- The structure of VCP. The six subunits are shown as molecular surface in different colors. Domains of each subunit are also shaded differently. Two views are presented. This structure represents VCP in an ADP bound state.

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. ^[19] 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, ^{[20] [21] [22] [23] [24]} 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 hydrolysis cycle

The ATP hydrolyzing activity is indispensable for the VCP functions. ^[25] 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. ^{[26] [27] [28] [29]} 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 ^[29] or by a putative substrate protein. ^[30] In Leishmania infantum, the LiVCP protein is essential for the intracellular development of the parasite and its survival under heat stress. ^[31] Association with cofactors can have either positive or negative impact on the p97 ATPase activity. ^{[32] [33]}

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. ^{[27] [34] [35]}

VCP-interacting proteins

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. ^{[36] [37] [38]} Examples of cofactors that interact with the carboxy-terminal tail of VCP are PLAA, PNGase, and Ufd2. ^{[39] [40] [41]}

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).

Figure 3- Structure of the N-domain of VCP. The N-domain is depicted as a molecular surface superimposed to a ribbon representation.

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) ^[42] and the other is termed VIM (VCP-interacting motif). ^[43] 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, ^[44] SVIP (small VCP-inhibiting protein) ^[45] and VIMP (VCP interacting membrane protein). ^[46] 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). ^[47] It was proposed that hierarchical binding to distinct cofactors may be essential for the broad functions of VCP. ^{[48] [49]}

Function

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.

Protein quality control

The best characterized function of VCP is to mediate a network of protein quality control processes in order to maintain protein homeostasis. ^[50] These include endoplasmic reticulum-associated protein degradation (ERAD) and mitochondria-associated degradation. ^{[14] [51]} 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. ^{[52] [53] [54]} 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. ^[55] 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. ^[56]

Chromatin-associated functions

VCP also functions broadly in eukaryotic nucleus by releasing protein molecules from chromatins in a manner analogous to that in ERAD. ^[57] 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.

Membrane fusion and trafficking

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. ^[58] 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. ^[56] 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. ^[59]

Clinical significance

Links to human diseases

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. ^[60] In 2010, mutations in VCP were also found to be a cause of amyotrophic lateral sclerosis by Bryan Traynor and Adriano Chiò. ^[61] 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. ^[62]

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. ^[63] 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. ^[64]

Cancer therapy

The first p97 inhibitor Eeyarestatin (EerI) was discovered by screening and characterizing compounds that inhibit the degradation of a fluorescence-labeled ERAD substrate. ^{[65] [66]} 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. ^[67] 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. ^{[68] [69] [70]} More recently, a potent and specific VCP inhibitor CB-5083 has been developed, which demonstrates promising anti-cancer activities in mouse xenograft tumor models. ^[71] The compound is now being evaluated in a phase 1 clinical trial. ^[72]

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Further reading

• Guinto JB, Ritson GP, Taylor JP, Forman MS (July 2007). "Valosin-containing protein and the pathogenesis of frontotemporal dementia associated with inclusion body myopathy". Acta Neuropathologica. 114 (1): 55–61. doi:10.1007/s00401-007-0224-7. PMID   17457594. S2CID   2094590.
• Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection. 24 (3): 317–20. doi:10.1016/S0163-4453(05)80037-4. PMID   1602151.
• Pleasure IT, Black MM, Keen JH (September 1993). "Valosin-containing protein, VCP, is a ubiquitous clathrin-binding protein". Nature. 365 (6445): 459–62. Bibcode:1993Natur.365..459P. doi:10.1038/365459a0. PMID   8413590. S2CID   4307576.
• Germain-Lee EL, Obie C, Valle D (August 1997). "NVL: a new member of the AAA family of ATPases localized to the nucleus". Genomics. 44 (1): 22–34. doi: 10.1006/geno.1997.4856 . PMID   9286697.
• Hoyle J, Tan KH, Fisher EM (October 1997). "Mapping the valosin-containing protein (VCP) gene on human chromosome 9 and mouse chromosome 4, and a likely pseudogene on the mouse X chromosome". Mammalian Genome. 8 (10): 778–80. doi:10.1007/s003359900566. PMID   9321476. S2CID   563437.
• Dai RM, Chen E, Longo DL, Gorbea CM, Li CC (February 1998). "Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome, in ubiquitin-proteasome-mediated degradation of IkappaBalpha". The Journal of Biological Chemistry. 273 (6): 3562–73. doi: 10.1074/jbc.273.6.3562 . PMID   9452483.
• Rabouille C, Kondo H, Newman R, Hui N, Freemont P, Warren G (March 1998). "Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro". Cell. 92 (5): 603–10. doi: 10.1016/S0092-8674(00)81128-9 . PMID   9506515. S2CID   17285800.
• Zhang SH, Liu J, Kobayashi R, Tonks NK (June 1999). "Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1". The Journal of Biological Chemistry. 274 (25): 17806–12. doi: 10.1074/jbc.274.25.17806 . PMID   10364224.
• Zhang H, Wang Q, Kajino K, Greene MI (May 2000). "VCP, a weak ATPase involved in multiple cellular events, interacts physically with BRCA1 in the nucleus of living cells". DNA and Cell Biology. 19 (5): 253–63. doi:10.1089/10445490050021168. PMID   10855792.
• Lavoie C, Chevet E, Roy L, Tonks NK, Fazel A, Posner BI, Paiement J, Bergeron JJ (December 2000). "Tyrosine phosphorylation of p97 regulates transitional endoplasmic reticulum assembly in vitro". Proceedings of the National Academy of Sciences of the United States of America. 97 (25): 13637–42. Bibcode:2000PNAS...9713637L. doi: 10.1073/pnas.240278097 . PMC   17628 . PMID   11087817.
• Seigneurin-Berny D, Verdel A, Curtet S, Lemercier C, Garin J, Rousseaux S, Khochbin S (December 2001). "Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways". Molecular and Cellular Biology. 21 (23): 8035–44. doi:10.1128/MCB.21.23.8035-8044.2001. PMC   99970 . PMID   11689694.
• Yang CS, Weiner H (April 2002). "Yeast two-hybrid screening identifies binding partners of human Tom34 that have ATPase activity and form a complex with Tom34 in the cytosol". Archives of Biochemistry and Biophysics. 400 (1): 105–10. doi:10.1006/abbi.2002.2778. PMID   11913976.
• Asai T, Tomita Y, Nakatsuka S, Hoshida Y, Myoui A, Yoshikawa H, Aozasa K (March 2002). "VCP (p97) regulates NFkappaB signaling pathway, which is important for metastasis of osteosarcoma cell line". Japanese Journal of Cancer Research. 93 (3): 296–304. doi:10.1111/j.1349-7006.2002.tb02172.x. PMC   5926968 . PMID   11927012.
• Kobayashi T, Tanaka K, Inoue K, Kakizuka A (December 2002). "Functional ATPase activity of p97/valosin-containing protein (VCP) is required for the quality control of endoplasmic reticulum in neuronally differentiated mammalian PC12 cells". The Journal of Biological Chemistry. 277 (49): 47358–65. doi: 10.1074/jbc.M207783200 . PMID   12351637.
• Uchiyama K, Jokitalo E, Kano F, Murata M, Zhang X, Canas B, Newman R, Rabouille C, Pappin D, Freemont P, Kondo H (December 2002). "VCIP135, a novel essential factor for p97/p47-mediated membrane fusion, is required for Golgi and ER assembly in vivo". The Journal of Cell Biology. 159 (5): 855–66. doi:10.1083/jcb.200208112. PMC   2173386 . PMID   12473691.

External links

• GeneReviews/NIH/NCBI/UW entry on Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia
• Overview of all the structural information available in the PDB for UniProt : P55072 (Transitional endoplasmic reticulum ATPase) at the PDBe-KB .