| Structural highlights
Disease
[TERA_HUMAN] Defects in VCP are the cause of inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) [MIM:167320]; also known as muscular dystrophy, limb-girdle, with Paget disease of bone or pagetoid amyotrophic lateral sclerosis or pagetoid neuroskeletal syndrome or lower motor neuron degeneration with Paget-like bone disease. IBMPFD features adult-onset proximal and distal muscle weakness (clinically resembling limb girdle muscular dystrophy), early-onset Paget disease of bone in most cases and premature frontotemporal dementia.[1] [2] [3] [4] [5] Defects in VCP are the cause of amyotrophic lateral sclerosis type 14 with or without frontotemporal dementia (ALS14) [MIM:613954]. ALS14 is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS14 may develop frontotemporal dementia.[6]
Function
[TERA_HUMAN] 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 UFD1L, 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-UFD1L-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 (By similarity). 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. Also involved in DNA damage response: recruited to double-strand breaks (DSBs) sites in a RNF8- and RNF168-dependent manner and promotes the recruitment of TP53BP1 at DNA damage sites. Recruited to stalled replication forks by SPRTN: may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.[7] [8] [9] [10] [11] [12] [13] [OTU1_YEAST] Hydrolase that can remove conjugated ubiquitin from proteins and may therefore play an important regulatory role at the level of protein turnover by preventing degradation. Participates in the regulation of the ubiquin conjugation pathway involving CDC48 by hindering multiubiquitination of substrates at the CDC48 chaperone. May be indireclty involved in PIS1 gene expression.[14] [15]
Publication Abstract from PubMed
Valosin-containing protein (VCP), also known as p97, is an AAA(+) ATPase that plays an essential role in a broad array of cellular processes including the endoplasmic reticulum-associated degradation (ERAD) pathway. Recently, ERAD-specific deubiquitinating enzymes have been reported to be physically associated with VCP, although the exact mechanism is not yet clear. Among these enzymes is ovarian tumor domain-containing protein 1 (OTU1). Here, we report the structural basis for interaction between VCP and OTU1. The crystal structure of the ubiquitin regulatory X-like (UBXL) domain of OTU1 (UBXLOTU1) complexed to the N-terminal domain of VCP (NVCP) at 1.8-A resolution reveals that UBXLOTU1 adopts a ubiquitin-like fold and binds at the interface of two subdomains of NVCP using the (39)GYPP(42) loop of UBXLOTU1 with the two prolines in cis- and trans-configurations, respectively. A mutagenesis study shows that this loop is not only critical for the interaction with VCP but also for its role in the ERAD pathway. Negative staining EM shows that one molecule of OTU1 binds to one VCP hexamer, and isothermal titration calorimetry suggests that the two proteins bind with a KD of 0.71 mum. Analytical size exclusion chromatography and isothermal titration calorimetry demonstrates that OTU1 can bind VCP in both the presence and absence of a heterodimer formed by ubiquitin fusion degradation protein 1 and nuclear localization protein 4.
Structural Basis for Ovarian Tumor Domain-containing Protein 1 (OTU1) Binding to p97/Valosin-containing Protein (VCP).,Kim SJ, Cho J, Song EJ, Kim SJ, Kim HM, Lee KE, Suh SW, Kim EE J Biol Chem. 2014 May 2;289(18):12264-74. doi: 10.1074/jbc.M113.523936. Epub 2014, Mar 7. PMID:24610782[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tang WK, Li D, Li CC, Esser L, Dai R, Guo L, Xia D. A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants. EMBO J. 2010 Jul 7;29(13):2217-29. Epub 2010 May 28. PMID:20512113 doi:10.1038/emboj.2010.104
- ↑ Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, Pestronk A, Whyte MP, Kimonis VE. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet. 2004 Apr;36(4):377-81. Epub 2004 Mar 21. PMID:15034582 doi:10.1038/ng1332
- ↑ Schroder R, Watts GD, Mehta SG, Evert BO, Broich P, Fliessbach K, Pauls K, Hans VH, Kimonis V, Thal DR. Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Ann Neurol. 2005 Mar;57(3):457-61. PMID:15732117 doi:10.1002/ana.20407
- ↑ Haubenberger D, Bittner RE, Rauch-Shorny S, Zimprich F, Mannhalter C, Wagner L, Mineva I, Vass K, Auff E, Zimprich A. Inclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene. Neurology. 2005 Oct 25;65(8):1304-5. PMID:16247064 doi:10.1212/01.wnl.0000180407.15369.92
- ↑ Weihl CC, Dalal S, Pestronk A, Hanson PI. Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum Mol Genet. 2006 Jan 15;15(2):189-99. Epub 2005 Dec 1. PMID:16321991 doi:10.1093/hmg/ddi426
- ↑ 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, Monsurro MR, Battistini S, Salvi F, Spataro R, Sola P, Borghero G, Galassi G, Scholz SW, Taylor JP, Restagno G, Chio A, Traynor BJ. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010 Dec 9;68(5):857-64. doi: 10.1016/j.neuron.2010.11.036. PMID:21145000 doi:10.1016/j.neuron.2010.11.036
- ↑ Ishigaki S, Hishikawa N, Niwa J, Iemura S, Natsume T, Hori S, Kakizuka A, Tanaka K, Sobue G. Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders. J Biol Chem. 2004 Dec 3;279(49):51376-85. Epub 2004 Sep 29. PMID:15456787 doi:10.1074/jbc.M406683200
- ↑ Song BL, Sever N, DeBose-Boyd RA. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell. 2005 Sep 16;19(6):829-40. PMID:16168377 doi:10.1016/j.molcel.2005.08.009
- ↑ Meerang M, Ritz D, Paliwal S, Garajova Z, Bosshard M, Mailand N, Janscak P, Hubscher U, Meyer H, Ramadan K. The ubiquitin-selective segregase VCP/p97 orchestrates the response to DNA double-strand breaks. Nat Cell Biol. 2011 Oct 23;13(11):1376-82. doi: 10.1038/ncb2367. PMID:22020440 doi:10.1038/ncb2367
- ↑ Acs K, Luijsterburg MS, Ackermann L, Salomons FA, Hoppe T, Dantuma NP. The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks. Nat Struct Mol Biol. 2011 Nov 27;18(12):1345-50. doi: 10.1038/nsmb.2188. PMID:22120668 doi:10.1038/nsmb.2188
- ↑ Sato T, Sako Y, Sho M, Momohara M, Suico MA, Shuto T, Nishitoh H, Okiyoneda T, Kokame K, Kaneko M, Taura M, Miyata M, Chosa K, Koga T, Morino-Koga S, Wada I, Kai H. STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein. Mol Cell. 2012 Jul 13;47(1):99-110. doi: 10.1016/j.molcel.2012.04.015. Epub 2012 , May 17. PMID:22607976 doi:10.1016/j.molcel.2012.04.015
- ↑ Davis EJ, Lachaud C, Appleton P, Macartney TJ, Nathke I, Rouse J. DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. Nat Struct Mol Biol. 2012 Nov;19(11):1093-100. doi: 10.1038/nsmb.2394. Epub 2012 , Oct 7. PMID:23042607 doi:10.1038/nsmb.2394
- ↑ Mosbech A, Gibbs-Seymour I, Kagias K, Thorslund T, Beli P, Povlsen L, Nielsen SV, Smedegaard S, Sedgwick G, Lukas C, Hartmann-Petersen R, Lukas J, Choudhary C, Pocock R, Bekker-Jensen S, Mailand N. DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. Nat Struct Mol Biol. 2012 Nov;19(11):1084-92. doi: 10.1038/nsmb.2395. Epub 2012, Oct 7. PMID:23042605 doi:10.1038/nsmb.2395
- ↑ Gardocki ME, Bakewell M, Kamath D, Robinson K, Borovicka K, Lopes JM. Genomic analysis of PIS1 gene expression. Eukaryot Cell. 2005 Mar;4(3):604-14. PMID:15755922 doi:10.1128/EC.4.3.604-614.2005
- ↑ Rumpf S, Jentsch S. Functional division of substrate processing cofactors of the ubiquitin-selective Cdc48 chaperone. Mol Cell. 2006 Jan 20;21(2):261-9. PMID:16427015 doi:S1097-2765(05)01897-6
- ↑ Kim SJ, Cho J, Song EJ, Kim SJ, Kim HM, Lee KE, Suh SW, Kim EE. Structural Basis for Ovarian Tumor Domain-containing Protein 1 (OTU1) Binding to p97/Valosin-containing Protein (VCP). J Biol Chem. 2014 May 2;289(18):12264-74. doi: 10.1074/jbc.M113.523936. Epub 2014, Mar 7. PMID:24610782 doi:http://dx.doi.org/10.1074/jbc.M113.523936
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