VCP (valosin containing protein)

Alias (NCBI)	ALS14
	IBMPFD
	TERA
	p97
HGNC (Hugo)	VCP
HGNC Alias symb	IBMPFD
	p97
	CDC48
	TERA
HGNC Alias name	transitional endoplasmic reticulum ATPase
HGNC Previous name	valosin-containing protein
LocusID (NCBI)	7415
Atlas_Id	42786
Location	9p13.3  [Link to chromosome band 9p13]
Location_base_pair	Starts at 35056066 and ends at 35072625 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping VCP.png]
	Genomic location of VCP/p97 gene at chromosome 9p13.3 (minus strand).

	A. The alignment of VCP/p97 mRNA to its genomic sequence. B. VCP/p97 mRNA and its amino acid coding.
Description	The p97/VCP gene spans a genomic region of 16674 bases on minus strand. The DNA of p97/VCP consists of 17 exons and the coding sequence starts in the first exon.
Transcription	The p97/VCP gene has one protein coding transcript which is 3859 bp long (Accession Number: NM_007126.3). The DNA has been cloned and sequenced by Koller and Brownstein in 1987 (Koller and Brownstein, 1987).
Pseudogene	According to Hoyle et al., p97/VCP has a mouse pseudogene namely Vcp-rs (valosin containing protein, related sequence) (Hoyle et al., 1997). For further information: Ensembl, Vega

	A schematic representation of the domain structure.
Description	VCP (Ter94 in D. melanogaster and CDC48 in S. cerevisiae) is a member of the AAA (ATPase associated with various cellular activities) ATPase family. It is one of the most abundant cytosolic proteins conserved throughout evolution from archaea to mammals. The complete protein contains 806 amino acids. The calculated molecular weight of p97/VCP is 89322 Da and the basal isoelectric point is 5.14. p97/VCP functions as a homohexamer composed of six subunits. Each protomer composed of four domains vital for its proper functioning, namely the N domain (1-187), D1 weak ATPase (209-460), D2 the major ATPase (481-761), and C (762-806) domains (DeLaBarre et al., 2006; Pye et al., 2007). p97/VCP gene consists of 17 coding exons. Its N domain is encoded by exons 1, 2, 3, 4 and 5, while the D1 and D2 domains are encoded by exons 6, 7, 8, 9, 10 and 12, 13, 14, respectively. There are two linker domains in the protein: N-D1 linker and flexible D1-D2 linker. The N domain of p97/VCP is responsible for the cofactor and ubiquitin binding function (Wang et al., 2003; Ye et al., 2003). While the D1 domain mediates oligomerization independent nucleotide binding, the D2 domain confers most of the ATPase activity (Wang et al., 2003). The two AAA domains contain the conserved Walker A, Walker B and a second region of homology (SRH). Walker A is required for nucleotide binding, whereas Walker B and SRH motifs mediate efficient ATP hydrolysis. ATP binding and hydrolysis lead to changes in the conformation of the hexameric ring, which is consistent with its role as a chaperone in disassembling protein complexes and mediating extraction of ubiquitinated proteins from the ER (Bays and Hampton, 2002; Rouiller et al., 2002).
Expression	Northern blot analyses showed that p97/VCP was ubiquitously expressed in all tissues and throughout the brain (Hirabayashi et al., 2001).
Localisation	Cytosol, nucleus. p97/VCP is recruited to the cytoplasmic surface of the ER via interaction with Endoplasmic reticulum-ubiquitin ligases.
Function	p97/VCP functions as segregase or unfoldase by utilizing the energy derived from ATP hydrolysis for conformational changes of target proteins. It is an essential protein having many roles in diverse biological processes, such as endoplasmic reticulum-associated degradation (ERAD), homotypic membrane fusion, transcriptional control, cell cycle regulation, autophagy, endosomal sorting and regulating protein degradation at the outer mitochondrial membrane (Woodman, 2003; Wang et al., 2004; Meyer et al., 2012). The diversity in cellular functions of p97/VCP is dictated by the variety of its interacting partner proteins. For example, p97/VCP has function in membrane fusion function via two different cofactors p47 and p37 (Uchiyama et al., 2006). The UBX-containing protein p47 functions together with p97/VCP in the fragmentation process of Golgi stacks during mitosis and for their reassembly after mitosis (Uchiyama et al., 2002; Uchiyama et al., 2003). The p97/VCP-p37 complex also brings about Golgi membrane fusion, however it might be required for organelle maintenance during interphase as well as their reassembly during mitosis (Uchiyama et al., 2006). p97/VCP has critical roles not only in Golgi membrane fusion but also in ER membrane fusion and nuclear assembly (Latterich et al., 1995; Hetzer et al., 2001). p97/VCP forms another complex with Ufd1-Npl4 dimer (Ye et al., 2001; Braun et al., 2002; Jarosch et al., 2002; Rabinovich et al., 2002). This complex is involved in regulating spindle disassembly at the end of mitosis, assembly of the nuclear envelope and retro-translocation during ERAD by binding ubiquitinated proteins and exporting them from the ER to the cytoplasm (Hetzer et al., 2001; Cao et al., 2003). Another molecular machinery where p97/VCP interacts with ubiquitin ligases, gp78 and Hrd1 functions in ERAD (Zhong et al., 2004; Lilley and Ploegh, 2005). Through this interaction p97/VCP is recruited from cytosol to the ER. The role of p97/VCP in ERAD is to interact with polyubiquitinated proteins and retrotranslocate them from ER to the cytosol. It has been recently suggested that Hrd1-mediated ERAD requires well-established retrotranslocation machinery, the p97/VCP-Ufd1-Npl4 complex, whereas the gp78 pathway needs only p97/VCP and Npl4 (Ballar et al., 2011). Another role of p97/VCP in ERAD is to bridge the ER to the proteasome by forming a complex with mHR23B (homolog of yeast Rad23)-PNGase (Li et al., 2005). p97/VCP is also indicated in autophagy where it is required for the autophagosome and lysosome fusion and this function is impaired with mutations in IBMPFD disease (Ju and Weihl, 2010; Tresse et al., 2010). Additionally, p97/VCP has role in endolysosomal sorting, where it binds to monoubiquitinated cargo, cavealin, on endosomes and functions in Cav1 transport to the endolysosomes (Ritz et al., 2011). There are several reports linking p97/VCP to the DNA repair mechanism (Ramadan, 2012). Ubiquitin binding domain containing DVC1 protein recruits p97/VCP to DNA damage sites, where p97/VCP facilitates the extraction of the translesion synthesis (TLS) polymerase (Pol) η during DNA repair (Davis et al., 2012). p97/VCP also promotes recruitment of human tumor suppressor 53BP1 by removing Polycomb protein L3MBTL1 from chromatin (Acs et al., 2011). p97/VCP has an essential role in DNA replication and cell cycle progression (Deichsel et al., 2009; Mouysset et al., 2008). Moreover, p97/VCP has a central regulatory role in the coordination of licensing and elongation events during eukaryotic DNA replication (Franz et al., 2011). A recently identified role of p97/VCP is related to mitophagy (Tanaka et al., 2010). The Vms-Npl4-Cdc48 complex organized upon mitochondrial stress plays a role in maintaining the mitochondrial function via protein quality control (Heo et al., 2010). p97/VCP also functions in degradation of mitochondrial proteins and retrotranslocates these proteins from mitochondria to the cytosol for proteasomal degradation (Xu et al., 2011).
Homology	Human p97/VCP gene is homolog to murine and rattus p97/VCP with 99.9pc.

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