| 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]
Publication Abstract from PubMed
p97/VCP is an essential cytosolic AAA+ ATPase hexamer that extracts and unfolds substrate polypeptides during protein homeostasis and degradation. Distinct sets of p97 adapters guide cellular functions but their roles in direct control of the hexamer are unclear. The UBXD1 adapter localizes with p97 in critical mitochondria and lysosome clearance pathways and contains multiple p97-interacting domains. We identify UBXD1 as a potent p97 ATPase inhibitor and report structures of intact p97:UBXD1 complexes that reveal extensive UBXD1 contacts across p97 and an asymmetric remodeling of the hexamer. Conserved VIM, UBX, and PUB domains tether adjacent protomers while a connecting strand forms an N-terminal domain lariat with a helix wedged at the interprotomer interface. An additional VIM-connecting helix binds along the second AAA+ domain. Together these contacts split the hexamer into a ring-open conformation. Structures, mutagenesis, and comparisons to other adapters further reveal how adapters containing conserved p97-remodeling motifs regulate p97 ATPase activity and structure.
The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions.,Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, Southworth DR bioRxiv. 2023 May 15:2023.05.15.540864. doi: 10.1101/2023.05.15.540864. Preprint. PMID:37292947[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Braxton JR, Altobelli CR, Tucker MR, Tse E, Thwin AC, Arkin MR, Southworth DR. The p97/VCP adapter UBXD1 drives AAA+ remodeling and ring opening through multi-domain tethered interactions. bioRxiv. 2023 May 15:2023.05.15.540864. PMID:37292947 doi:10.1101/2023.05.15.540864
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