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P97 VCP

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https://www.readbyqxmd.com/read/29359838/discrimination-between-the-er-and-mitochondria-by-spontaneously-inserting-tail-anchored-proteins
#1
Bruna Figueiredo Costa, Patrizia Cassella, Sara Francesca Colombo, Nica Borgese
Tail-anchored (TA) proteins insert into their target organelles by incompletely elucidated post-translational pathways. Some TA proteins spontaneously insert into protein-free liposomes, yet target a specific organelle in vivo. Two spontaneously inserting cytochrome b5 forms, b5-ER and b5-RR, which differ only in the charge of the C-terminal region, target the ER or the mitochondrial outer membrane (MOM), respectively. To bridge the gap between the cell-free and in cellula results, we analyzed targeting in digitonin-permeabilized adherent HeLa cells...
January 23, 2018: Traffic
https://www.readbyqxmd.com/read/29320735/rybp-is-a-k63-ubiquitin-chain-binding-protein-that-inhibits-homologous-recombination-repair
#2
Mohammad A M Ali, Hilmar Strickfaden, Brian L Lee, Leo Spyracopoulos, Michael J Hendzel
Ring1-YY1-binding protein (RYBP) is a member of the non-canonical polycomb repressive complex 1 (PRC1), and like other PRC1 members, it is best described as a transcriptional regulator. However, several PRC1 members were recently shown to function in DNA repair. Here, we report that RYBP preferentially binds K63-ubiquitin chains via its Npl4 zinc finger (NZF) domain. Since K63-linked ubiquitin chains are assembled at DNA double-strand breaks (DSBs), we examined the contribution of RYBP to DSB repair. Surprisingly, we find that RYBP is K48 polyubiquitylated by RNF8 and rapidly removed from chromatin upon DNA damage by the VCP/p97 segregase...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29238611/structural-basis-for-nucleotide-modulated-p97-association-with-the-er-membrane
#3
Wai Kwan Tang, Ting Zhang, Yihong Ye, Di Xia
Association of the cytosolic AAA (ATPases associated with various cellular activities) protein p97 to membranes is essential for various cellular processes including endoplasmic reticulum (ER)-associated degradation. The p97 consists of two ATPase domains and an N domain that interacts with numerous cofactors. The N domain of p97 is known to undergo a large nucleotide-dependent conformation switch, but its physiological relevance is unclear. Here we show p97 is recruited to canine ER membranes predominantly by interacting with VCP-interacting membrane protein (VIMP), an ER-resident protein...
2017: Cell Discovery
https://www.readbyqxmd.com/read/29211715/alcohol-abuse-drug-disulfiram-targets-cancer-via-p97-segregase-adaptor-npl4
#4
Zdenek Skrott, Martin Mistrik, Klaus Kaae Andersen, Søren Friis, Dusana Majera, Jan Gursky, Tomas Ozdian, Jirina Bartkova, Zsofia Turi, Pavel Moudry, Marianne Kraus, Martina Michalova, Jana Vaclavkova, Petr Dzubak, Ivo Vrobel, Pavla Pouckova, Jindrich Sedlacek, Andrea Miklovicova, Anne Kutt, Jing Li, Jana Mattova, Christoph Driessen, Q Ping Dou, Jørgen Olsen, Marian Hajduch, Boris Cvek, Raymond J Deshaies, Jiri Bartek
Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis...
December 6, 2017: Nature
https://www.readbyqxmd.com/read/29153394/vcp-p97-mediated-unfolding-as-a-principle-in-protein-homeostasis-and-signaling
#5
REVIEW
Johannes van den Boom, Hemmo Meyer
The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins...
January 18, 2018: Molecular Cell
https://www.readbyqxmd.com/read/28949448/vcp-inhibitors-induce-endoplasmic-reticulum-stress-cause%C3%A2-cell-cycle-arrest-trigger-caspase-mediated-cell-death%C3%A2-and-synergistically-kill-ovarian-cancer-cells-in-combination-with-salubrinal
#6
(no author information available yet)
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
December 2016: Molecular Oncology
https://www.readbyqxmd.com/read/28939772/interaction-between-the-aaa-atpase-p97-and-its-cofactor-ataxin3-in-health-and-disease-nucleotide-induced-conformational-changes-regulate-cofactor-binding
#7
Maya V Rao, Dewight R Williams, Simon Cocklin, Patrick J Loll
p97 is an essential ATPase associated with various cellular activities (AAA(+)) that functions as a segregase in diverse cellular processes, including the maintenance of proteostasis. p97 interacts with different cofactors that target it to distinct pathways; an important example is the deubiquitinase ataxin3, which collaborates with p97 in endoplasmic reticulum-associated degradation. However, the molecular details of this interaction have been unclear. Here, we characterized the binding of ataxin3 to p97, showing that ataxin3 binds with low-micromolar affinity to both wild-type p97 and mutants linked to degenerative disorders known as multisystem proteinopathy 1 (MSP1); we further showed that the stoichiometry of binding is one ataxin3 molecule per p97 hexamer...
November 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28815021/toward-an-understanding-of-the-cdc48-p97-atpase
#8
REVIEW
Nicholas Bodnar, Tom Rapoport
A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. For example, in endoplasmic reticulum (ER)-associated protein degradation (ERAD), Cdc48/p97 pulls polyubiquitinated, misfolded proteins out of the ER and transfers them to the proteasome. Cdc48/p97 consists of an N-terminal domain and two ATPase domains (D1 and D2). Six Cdc48 monomers form a double-ring structure surrounding a central pore...
2017: F1000Research
https://www.readbyqxmd.com/read/28794043/sorafenib-impedes-rift-valley-fever-virus-egress-by-inhibiting-valosin-containing-protein-function-in-the-cellular-secretory-pathway
#9
Ashwini Brahms, Rajini Mudhasani, Chelsea Pinkham, Krishna Kota, Farooq Nasar, Rouzbeh Zamani, Sina Bavari, Kylene Kehn-Hall
There is an urgent need for therapeutic development to combat infections caused by Rift Valley fever virus (RVFV), which causes devastating disease in both humans and animals. In an effort to repurpose drugs for RVFV treatment, our previous studies screened a library of FDA-approved drugs. The most promising candidate identified was the hepatocellular and renal cell carcinoma drug sorafenib. Mechanism-of-action studies indicated that sorafenib targeted a late stage in virus infection and caused a buildup of virions within cells...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28760999/exploiting-conformational-plasticity-in-the-aaa-protein-vcp-p97-to-modify-function
#10
Anne Kathrin Schütz, Enrico Rennella, Lewis E Kay
p97/VCP, a member of the AAA+ (ATPases associated with diverse cellular activities) family of proteins, is implicated in the etiology of a group of degenerative diseases affecting bone and muscle tissue as well as the central nervous system. Methyl-TROSY-based NMR studies have previously revealed how disease-causing mutations deregulate a subtle dynamic conformational equilibrium involving the N-terminal domain (NTD) with implications for the binding of certain adaptors, providing insight into how disease mutations lead to abnormal function...
July 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28691899/aggregation-of-a-hepatitis-c-virus-replicase-module-induced-by-ablation-of-p97-vcp
#11
Zhigang Yi, Zhenghong Yuan
Hijacking host membranes to assemble a membrane-associated viral replicase is a hallmark of almost all positive-strand RNA viruses. However, how the virus co-opts host factors to facilitate this energy-unfavourable process is incompletely understood. In a previous study, using hepatitis C virus (HCV) as a model and employing affinity purification of the viral replicase, we identified a valosin-containing protein (p97/VCP), a member of the ATPases associated with diverse cellular activities (AAA+ ATPase family), as a viral replicase-associated host factor...
July 2017: Journal of General Virology
https://www.readbyqxmd.com/read/28689657/wnt-dependent-inactivation-of-the-groucho-tle-co-repressor-by-the-hect-e3%C3%A2-ubiquitin-ligase-hyd-ubr5
#12
Joshua E Flack, Juliusz Mieszczanek, Nikola Novcic, Mariann Bienz
Extracellular signals are transduced to the cell nucleus by effectors that bind to enhancer complexes to operate transcriptional switches. For example, the Wnt enhanceosome is a multiprotein complex associated with Wnt-responsive enhancers through T cell factors (TCF) and kept silent by Groucho/TLE co-repressors. Wnt-activated β-catenin binds to TCF to overcome this repression, but how it achieves this is unknown. Here, we discover that this process depends on the HECT E3 ubiquitin ligase Hyd/UBR5, which is required for Wnt signal responses in Drosophila and human cell lines downstream of activated Armadillo/β-catenin...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28660197/a-mighty-protein-extractor-of-the-cell-structure-and-function-of-the-p97-cdc48-atpase
#13
REVIEW
Yihong Ye, Wai Kwan Tang, Ting Zhang, Di Xia
p97/VCP (known as Cdc48 in S. cerevisiae or TER94 in Drosophila) is one of the most abundant cytosolic ATPases. It is highly conserved from archaebacteria to eukaryotes. In conjunction with a large number of cofactors and adaptors, it couples ATP hydrolysis to segregation of polypeptides from immobile cellular structures such as protein assemblies, membranes, ribosome, and chromatin. This often results in proteasomal degradation of extracted polypeptides. Given the diversity of p97 substrates, this "segregase" activity has profound influence on cellular physiology ranging from protein homeostasis to DNA lesion sensing, and mutations in p97 have been linked to several human diseases...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28611990/structure-and-function-of-p97-and-pex1-6-type-ii-aaa-complexes
#14
REVIEW
Paul Saffert, Cordula Enenkel, Petra Wendler
Protein complexes of the Type II AAA+ (ATPases associated with diverse cellular activities) family are typically hexamers of 80-150 kDa protomers that harbor two AAA+ ATPase domains. They form double ring assemblies flanked by associated domains, which can be N-terminal, intercalated or C-terminal to the ATPase domains. Most prominent members of this family include NSF (N-ethyl-maleimide sensitive factor), p97/VCP (valosin-containing protein), the Pex1/Pex6 complex and Hsp104 in eukaryotes and ClpB in bacteria...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28575658/rfwd3-mediated-ubiquitination-promotes-timely-removal-of-both-rpa-and-rad51-from-dna-damage-sites-to-facilitate-homologous-recombination
#15
Shojiro Inano, Koichi Sato, Yoko Katsuki, Wataru Kobayashi, Hiroki Tanaka, Kazuhiro Nakajima, Shinichiro Nakada, Hiroyuki Miyoshi, Kerstin Knies, Akifumi Takaori-Kondo, Detlev Schindler, Masamichi Ishiai, Hitoshi Kurumizaka, Minoru Takata
RFWD3 is a recently identified Fanconi anemia protein FANCW whose E3 ligase activity toward RPA is essential in homologous recombination (HR) repair. However, how RPA ubiquitination promotes HR remained unknown. Here, we identified RAD51, the central HR protein, as another target of RFWD3. We show that RFWD3 polyubiquitinates both RPA and RAD51 in vitro and in vivo. Phosphorylation by ATR and ATM kinases is required for this activity in vivo. RFWD3 inhibits persistent mitomycin C (MMC)-induced RAD51 and RPA foci by promoting VCP/p97-mediated protein dynamics and subsequent degradation...
June 1, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28551275/genetic-analysis-of-vcp-and-wash-complex-genes-in-a-german-cohort-of-sporadic-als-ftd-patients
#16
Matthias Türk, Rolf Schröder, Katharina Khuller, Andreas Hofmann, Carolin Berwanger, Albert C Ludolph, Gabriele Dekomien, Kathrin Müller, Jochen H Weishaupt, Christian T Thiel, Christoph S Clemen
Mutations of the human valosin-containing protein, p97 (VCP) and Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex genes cause motor neuron and cognitive impairment disorders. Here, we analyzed a cohort of German patients with sporadic amyotrophic lateral sclerosis and frontotemporal lobar degeneration comorbidity (ALS/FTD) for VCP and WASH complex gene mutations. Next-generation panel sequencing of VCP, WASH1, FAM21C, CCDC53, SWIP, strumpellin, F-actin capping protein of muscle Z-line alfa 1 (CAPZA1), and CAPZB genes was performed in 43 sporadic ALS/FTD patients...
May 3, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28512218/ubiquitin-and-atp-dependent-unfoldase-activity-of-p97-vcp%C3%A2-nploc4%C3%A2-ufd1l-is-enhanced-by-a-mutation-that-causes-multisystem-proteinopathy
#17
Emily E Blythe, Kristine C Olson, Vincent Chau, Raymond J Deshaies
p97 is a "segregase" that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28494016/the-host-ubiquitin-dependent-segregase-vcp-p97-is-required-for-the-onset-of-human-cytomegalovirus-replication
#18
Yao-Tang Lin, James Prendergast, Finn Grey
The human cytomegalovirus major immediate early proteins IE1 and IE2 are critical drivers of virus replication and are considered pivotal in determining the balance between productive and latent infection. IE1 and IE2 are derived from the same primary transcript by alternative splicing and regulation of their expression likely involves a complex interplay between cellular and viral factors. Here we show that knockdown of the host ubiquitin-dependent segregase VCP/p97, results in loss of IE2 expression, subsequent suppression of early and late gene expression and, ultimately, failure in virus replication...
May 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28475898/molecular-mechanism-of-substrate-processing-by-the-cdc48-atpase-complex
#19
Nicholas O Bodnar, Tom A Rapoport
The Cdc48 ATPase and its cofactors Ufd1/Npl4 (UN) extract polyubiquitinated proteins from membranes or macromolecular complexes, but how they perform these functions is unclear. Cdc48 consists of an N-terminal domain that binds UN and two stacked hexameric ATPase rings (D1 and D2) surrounding a central pore. Here, we use purified components to elucidate how the Cdc48 complex processes substrates. After interaction of the polyubiquitin chain with UN, ATP hydrolysis by the D2 ring moves the polypeptide completely through the double ring, generating a pulling force on the substrate and causing its unfolding...
May 4, 2017: Cell
https://www.readbyqxmd.com/read/28451587/the-interplay-of-cofactor-interactions-and-post-translational-modifications-in-the-regulation-of-the-aaa-atpase-p97
#20
REVIEW
Petra Hänzelmann, Hermann Schindelin
The hexameric type II AAA ATPase (ATPase associated with various activities) p97 (also referred to as VCP, Cdc48, and Ter94) is critically involved in a variety of cellular activities including pathways such as DNA replication and repair which both involve chromatin remodeling, and is a key player in various protein quality control pathways mediated by the ubiquitin proteasome system as well as autophagy. Correspondingly, p97 has been linked to various pathophysiological states including cancer, neurodegeneration, and premature aging...
2017: Frontiers in Molecular Biosciences
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