Transitional endoplasmic reticulum ATPase (VCP)
The protein contains 806 amino acids for an estimated molecular weight of 89322 Da.
Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional elements of the endoplasmic reticulum (tER). Vesicle budding from the tER is an ATP-dependent process. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. Regulates E3 ubiquitin-protein ligase activity of RNF19A. Component of the VCP/p97-AMFR/gp78 complex that participates in the final step of the sterol-mediated ubiquitination and endoplasmic reticulum-associated degradation (ERAD) of HMGCR. Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908). Plays a role in the regulation of stress granules (SGs) clearance process upon arsenite-induced response (PubMed:29804830). Also involved in DNA damage response: recruited (updated: Nov. 7, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
Biological Process
Activation of cysteine-type endopeptidase activity involved in apoptotic process
Aggresome assembly
ATP metabolic process
Autophagosome maturation
Autophagy
Cellular response to arsenite ion
Cellular response to DNA damage stimulus
Cellular response to heat
DNA repair
Double-strand break repair
Endoplasmic reticulum stress-induced pre-emptive quality control
Endoplasmic reticulum to Golgi vesicle-mediated transport
Endoplasmic reticulum unfolded protein response
Endosome to lysosome transport via multivesicular body sorting pathway
ER-associated misfolded protein catabolic process
ERAD pathway
Error-free translesion synthesis
Establishment of protein localization
Flavin adenine dinucleotide catabolic process
Interstrand cross-link repair
Macroautophagy
Mitotic spindle disassembly
NADH metabolic process
Negative regulation of smoothened signaling pathway
Neutrophil degranulation
Positive regulation of ATP biosynthetic process
Positive regulation of canonical Wnt signaling pathway
Positive regulation of Lys63-specific deubiquitinase activity
Positive regulation of mitochondrial membrane potential
Positive regulation of oxidative phosphorylation
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process
Positive regulation of protein catabolic process
Positive regulation of protein K63-linked deubiquitination
Positive regulation of protein-containing complex assembly
Proteasomal protein catabolic process
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein deubiquitination
Protein folding
Protein hexamerization
Protein homooligomerization
Protein methylation
Protein N-linked glycosylation via asparagine
Protein ubiquitination
Protein-DNA covalent cross-linking repair
Regulation of aerobic respiration
Regulation of apoptotic process
Regulation of protein localization to chromatin
Regulation of synapse organization
Retrograde protein transport, ER to cytosol
Stress granule disassembly
Translesion synthesis
Transmembrane transport
Ubiquitin-dependent ERAD pathway
Viral genome replication
Cellular Component
ATPase complex
Azurophil granule lumen
Cytoplasm
Cytoplasmic stress granule
Cytosol
Derlin-1 retrotranslocation complex
Endoplasmic reticulum
Endoplasmic reticulum membrane
Extracellular exosome
Extracellular region
Ficolin-1-rich granule lumen
Glutamatergic synapse
Hrd1p ubiquitin ligase complex
Intracellular membrane-bounded organelle
Lipid droplet
Myelin sheath
Nucleoplasm
Nucleus
Perinuclear region of cytoplasm
Proteasome complex
Protein complex
Protein-containing complex
Secretory granule lumen
Site of double-strand break
Synapse
VCP-NPL4-UFD1 AAA ATPase complex
VCP-NSFL1C complex
Molecular Function
ADP binding
ATP binding
ATPase
BAT3 complex binding
Deubiquitinase activator activity
Identical protein binding
K48-linked polyubiquitin modification-dependent protein binding
Lipid binding
MHC class I protein binding
Poly(A) RNA binding
Polyubiquitin modification-dependent protein binding
Protein domain specific binding
Protein phosphatase binding
RNA binding
Ubiquitin protein ligase binding
Ubiquitin-like protein ligase binding
Ubiquitin-specific protease binding
The reference OMIM entry for this protein is 167320
Inclusion body myopathy with early-onset paget disease with or without frontotemporal dementia 1; ibmpfd1
Multisystem proteinopathy 1; msp1
Muscular dystrophy, limb-girdle, with paget disease of bone
Pagetoid amyotrophic lateral sclerosis
Pag
A number sign (#) is used with this entry because inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD1) is caused by heterozygous mutation in the VCP gene (601023) on chromosome 9p13. See also amyotrophic lateral sclerosis-14 with or without frontotemporal dementia (ALS14; 613954), which is also caused by heterozygous mutation in the VCP gene and can show overlapping clinical features.
DESCRIPTION
IBMPFD is an autosomal dominant disorder characterized by incomplete penetrance of 3 main features: disabling muscle weakness (in 90%), osteolytic bone lesions consistent with Paget disease (in 51%), and frontotemporal dementia (in 32%). Muscle weakness is an isolated symptom in about 30% of patients and the presenting symptom in greater than half of patients, suggesting that IBMPFD may commonly be seen in a neuromuscular clinic without its other syndromic features (review by Weihl et al., 2009). - Genetic Heterogeneity of IBMPFD IBMPFD2 (615422) is caused by mutation in the HNRNPA2B1 gene (600124) on chromosome 7p15. IBMPFD3 (615424) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13.CLINICAL FEATURES
Tucker et al. (1982) studied a large kindred with a syndrome of lower motor neuron degeneration and polyostotic skeletal disorganization resembling Paget disease of bone (PDB; see 167250). The disorder begins insidiously at about age 35 with weakness and atrophy of the leg and proximal arm muscles. Nerve conductions are normal; EMG shows muscle denervation, as does muscle biopsy. The disorder progresses to wheelchair confinement and later to bed confinement, quadriparesis, dementia, respiratory failure, and death before age 60 years. Even early in the neurologic illness, patients have coarse trabeculation, cortical thickening, and spotty sclerosis on bone x-rays; diffusely increased uptake of radionuclide and elevated heat-labile serum alkaline phosphatase. The disorder affected 6 females and 6 males in 5 sibships of 3 generations with no instance of male-to-male transmission. Kimonis et al. (2000) described a family in which autosomal dominant limb-girdle muscular dystrophy (LGMD) was associated with early-onset Paget disease of bone PDB and cardiomyopathy. Eight of 11 affected individuals had both disorders. Onset of PDB occurred at a mean age of 35 years, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy was progressive with mildly elevated to normal CPK levels. Muscle biopsy in the oldest male revealed vacuolated fibers, but in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness and respiratory and cardiac failure in their forties to sixties. Kovach et al. (2001) described the clinical, biochemical, radiologic, and pathologic characteristics of 49 affected individuals from the family described by Kimonis et al. (2000) and 3 other unrelated families with autosomal dominant inclusion body myopathy (IBM), PDB, and frontotemporal dementia. Ninety percent of the patients had myopathy, 43% had PDB, and 37% had premature frontotemporal dementia. Watts et al. (2004) reported 13 families with IBMPFD, 12 from the U.S. and 1 from Canada. Among those individuals, 82% of affected individuals had myopathy, 49% had PDB, and 30% had early-onset frontotemporal dementia. The mean age at presentation was 42 years for both IBM and PDB, whereas frontotemporal dementia typically presented at age 53 years. In ... More on the omim web site
May 13, 2019: Protein entry updated
Automatic update: model status changed
Nov. 17, 2018: Protein entry updated
Automatic update: model status changed
Nov. 16, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Oct. 27, 2017: Protein entry updated
Automatic update: model status changed
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 167320 was added.
Sept. 16, 2015: Protein entry updated
Automatic update: model status changed