Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the cloning and characterization of a cDNA encoding the valosin-containing protein (VCP) from the Haemaphysalis longicornis tick (HlVCP). The full-length HlVCP is 2782 bp and codes for 808 amino acids of a deduced protein with a predicted molecular mass of 89.9 kDa. The domain structure analysis revealed that the deduced protein has 2 Walker A domains, 2 Walker B domains, a Cdc48 domain, and a polyQ-binding domain. The mouse anti-HlVCP serum recognized a 97 kDa native protein in the salivary glands, midgut, and synganglion. RT-PCR analysis revealed that the native VCP was expressed throughout the developing stages and in tick organs. HlVCP silencing resulted in a decrease in tick body mass after blood feeding. This study not only contributes to a growing understanding of the ATPase gene family but also lays the groundwork for future studies on protein secretion and host-tick interaction. This study is the first report of the VCP gene from Chelicerata, which include spiders, scorpions, and ticks.
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PMID:Valosin-containing protein from the hard tick Haemaphysalis longicornis: effects of dsRNA-mediated HlVCP gene silencing. 1761 33

The elimination of misfolded proteins, known as protein quality control, is an essential cellular process. Removal of misfolded proteins from the secretory pathway depends on their recognition in the endoplasmic reticulum (ER) followed by their retrograde transport into the cytosol for degradation. The AAA-ATPase Cdc48/p97 facilitates the translocation of misfolded ER-proteins into the cytosol. Cdc48/p97 can dock onto the ER-membrane via direct interaction with ER-membrane proteins and/or indirectly via its substrate-recruiting cofactors, which interact with the ubiquitylated substrates at the membrane. This tight interaction in conjunction with the conformational changes induced upon ATP hydrolysis within Cdc48/p97 is thought to provide the driving force for the translocation reaction. Subsequently, a series of protein-protein interactions between the Cdc48/p97 complex, its cofactors, and the ubiquitylated substrates is instrumental for the proper delivery of the ER substrates to the proteasome. These protein-protein interactions are governed mainly by ubiquitin-fold and ubiquitin-binding domains.
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PMID:Ubiquitin receptors and ERAD: a network of pathways to the proteasome. 1794 49

During division of metazoan cells, the nucleus disassembles to allow chromosome segregation, and then reforms in each daughter cell. Reformation of the nucleus involves chromatin decondensation and assembly of the double-membrane nuclear envelope around the chromatin; however, regulation of the process is still poorly understood. In vitro, nucleus formation requires p97 (ref. 3), a hexameric ATPase implicated in membrane fusion and ubiquitin-dependent processes. However, the role and relevance of p97 in nucleus formation have remained controversial. Here we show that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B. During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. These data reveal an essential pathway that regulates reformation of the nucleus after mitosis and defines ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation.
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PMID:Cdc48/p97 promotes reformation of the nucleus by extracting the kinase Aurora B from chromatin. 1809 15

Endoplasmic reticulum (ER)-associated degradation (ERAD) eliminates aberrant proteins from the ER by dislocating them to the cytoplasm where they are tagged by ubiquitin and degraded by the proteasome. Six distinct AAA-ATPases (Rpt1-6) at the base of the 19S regulatory particle of the 26S proteasome recognize, unfold, and translocate substrates into the 20S catalytic chamber. Here we show unique contributions of individual Rpts to ERAD by employing equivalent conservative substitutions of the invariant lysine in the ATP-binding motif of each Rpt subunit. ERAD of two substrates, luminal CPY*-HA and membrane 6myc-Hmg2, is inhibited only in rpt4R and rpt2RF mutants. Conversely, in vivo degradation of a cytosolic substrate, DeltassCPY*-GFP, as well as in vitro cleavage of Suc-LLVY-AMC are hardly affected in rpt4R mutant yet are inhibited in rpt2RF mutant. Together, we find that equivalent mutations in RPT4 and RPT2 result in different phenotypes. The Rpt4 mutation is manifested in ERAD defects, whereas the Rpt2 mutation is manifested downstream, in global proteasomal activity. Accordingly, rpt4R strain is particularly sensitive to ER stress and exhibits an activated unfolded protein response, whereas rpt2RF strain is sensitive to general stress. Further characterization of Rpt4 involvement in ERAD reveals that it participates in CPY*-HA dislocation, a function previously attributed to p97/Cdc48, another AAA-ATPase essential for ERAD of CPY*-HA but dispensable for proteasomal degradation of DeltassCPY*-GFP. Pointing to Cdc48 and Rpt4 overlapping functions, excess Cdc48 partially restores impaired ERAD in rpt4R, but not in rpt2RF. We discuss models for Cdc48 and Rpt4 cooperation in ERAD.
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PMID:A proteasomal ATPase contributes to dislocation of endoplasmic reticulum-associated degradation (ERAD) substrates. 1817 73

Abnormal protein aggregates are commonly observed in affected neurons in many neurodegenerative disorders. We have reported that VCP (valosin-containing protein) co-localizes with protein aggregates in neurons of patients and in cultured cells expressing diseased proteins. However, the significance of such co-localization remains to be elucidated. In the present paper, I discuss the involvement of VCP in the processes of both the formation and re-solubilization of abnormal protein aggregates. In the study, VCP recognized and accumulated on to pre-formed protein aggregates created by proteasome inhibition. VCP knockdown or expression of dominant-negative VCP both significantly delayed the elimination of ubiquitin-positive aggregates. VCP was also involved in the clearance of pre-formed polyglutamine aggregates. Paradoxically, VCP knockdown also diminished polyglutamine aggregate formation. Furthermore, its ATPase activity is required for the re-solubilization and reactivation of heat-denatured proteins, such as luciferase, from insoluble aggregates. We thus propose that VCP functions as a mediator for both aggregate formation and clearance, depending on the concentration of soluble aggregate-prone proteins, indicating that VCP has dual functions as an aggregate formase and an unfoldase. We then examined the potentially elevated aggregate formase activities of mutant VCPs, which have been found to cause IBMPFD (inclusion body myopathy, Paget disease of bone and front-temporal dementia). Indeed, all IBMPFD VCPs showed elevated aggregate formase activities on both polyglutamine and proteasome inhibitor-mediated aggregates. Biochemically, all IBMPFD VCPs showed elevated ATPase activities as well as elevated binding affinities not only for several VCP cofactors, but also for ubiquitinated proteins. Thus controlling the function of VCP, namely decreasing aggregate formase activities and/or increasing unfoldase activities, is expected to be of great benefit for the treatment of IBMPFD and also several neurodegenerative disorders with intracellular protein inclusions.
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PMID:Roles of VCP in human neurodegenerative disorders. 1820 95

To identify new components of the protein quality control and degradation pathway of the endoplasmic reticulum (ER), we performed a growth-based genome-wide screen of about 5000 viable deletion mutants of the yeast Saccharomyces cerevisiae. As substrates we used two misfolded ER membrane proteins, CTL* and Sec61-2L, chimeric derivatives of the classical ER degradation substrates CPY* and Sec61-2. Both substrates contain a cytosolic Leu2 protein fusion, and stabilization of these substrates in ER-associated degradation-deficient strains enables a restored growth of the transformed LEU2-deficient deletion mutants. We identified the strain deleted for the ubiquitin chain elongating ligase Hul5 among the mutant strains with a strong growth phenotype. Here we show that Hul5 is necessary for the degradation of two misfolded ER membrane substrates. Although the degradation of their N-terminal parts is Hul5-independent, the breakdown of their C-terminal fragments requires the ubiquitin chain elongating ligase activity of Hul5. In the absence of Hul5, a truncated form of CTL*myc remains to a large extent embedded in the ER membrane. Hul5 activity promotes the interaction of this truncated CTL*myc with the AAA-ATPase Cdc48, which is known to pull proteins out of the ER membrane. This study unravels the stepwise elimination of the ER membrane-localized CTL*myc substrate. First, N-terminal, lumenal CPY* is transferred to the cytoplasm and degraded by the proteasome. Subsequently, the remaining C-terminal membrane-anchored part requires Hul5 for its effective extraction out of the endoplasmic reticulum and proteasomal degradation.
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PMID:Ubiquitin ligase Hul5 is required for fragment-specific substrate degradation in endoplasmic reticulum-associated degradation. 1843 32

The highly conserved AAA ATPase Cdc48/p97 acts on ubiquitylated substrate proteins in cellular processes as diverse as the fusion of homotypic membranes and the degradation of misfolded proteins. The 'Ubiquitin regulatory X' (UBX) domain-containing proteins constitute the so far largest family of Cdc48/p97 cofactors. UBX proteins are involved in substrate recruitment to Cdc48/p97 and in the temporal and spatial regulation of its activity. In combination with UBX-like proteins and other cofactors, they can assemble into a large variety of Cdc48/p97-cofactor complexes possessing distinct cellular functions. This review gives an overview of the different subfamilies of UBX proteins and their functions, and discusses general principles of Cdc48/p97 regulation by these cofactors.
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PMID:UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97. 1843 7

The AAA ATPase complex known as p97 or VCP in mammals and Cdc48 in yeast is connected to a multitude of cellular pathways, including membrane fusion, protein folding, protein degradation and activation of membrane-bound transcription factors. The mechanism by which p97 participates in such a broad spectrum of cellular functions appears to be via recruiting certain specific co-factors. Here we isolate and characterize the human protein Ubxd1, a novel co-factor of p97. We show that Ubxd1 is a stable protein that localizes to the cytoplasm and nucleus and is highly enriched in centrosomes. In mice Ubxd1 is widely expressed, but especially abundant in brain. Curiously, Ubxd1 does not associate with p97 via its UBX domain, but via its PUB domain which binds the extreme C-terminus of p97. Phosphorylation of the penultimate tyrosine residue in p97 completely abolishes Ubxd1 interaction. Ternary complexes of Ubxd1, p47, and p97 were detected in vitro. Inhibition of Ubxd1 expression by siRNA did not affect the degradation of bulk protein or a model substrate of the ERAD pathway, indicating that Ubxd1 directs p97 activity to specialized functions in vivo.
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PMID:Ubxd1 is a novel co-factor of the human p97 ATPase. 1865 46

Since cdc48 mutants were isolated by the first genetic screens for cell division cycle (cdc) mutants in yeast, the requirement of the chaperone-like ATPase Cdc48/p97 during cell division has remained unclear. Here, we discover an unanticipated function for Caenorhabditis elegans CDC-48 in DNA replication linked to cell cycle control. Our analysis of the CDC-48(UFD-1/NPL-4) complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms. These developmental defects result from activation of the DNA replication checkpoint caused by replication stress. Similar to loss of replication licensing factors, DNA content is strongly reduced in worms depleted for CDC-48, UFD-1, and NPL-4. In addition, these worms show decreased DNA synthesis and hypersensitivity toward replication blocking agents. Our findings identified a role for CDC-48(UFD-1/NPL-4) in DNA replication, which is important for cell cycle progression and genome stability.
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PMID:Cell cycle progression requires the CDC-48UFD-1/NPL-4 complex for efficient DNA replication. 1872 80

Thermoacidophilic crenarchaea of the genus Sulfolobus contain six AAA (ATPase associated with various cellular activities) proteins, including a proteasome-associated ATPase, a Vps4 (vacuolar protein sorting 4) homologue, and two Cdc48 (cell-division cycle 48)-like proteins. The last two AAA proteins are deeply branching divergent members of this family without close relatives outside the Sulfolobales. Both proteins have two nucleotide-binding domains and, unlike other members of the family, they seem to lack folded N-terminal domains. Instead, they contain N-terminal extensions of approx. 50 residues, which are predicted to be unstructured, except for a single transmembrane helix. We have analysed the two proteins, MBA (membrane-bound AAA) 1 and MBA2, by computational and experimental means. They appear to be monophyletic and to share a common ancestor with the Cdc48 clade. Both are membrane-bound and active as nucleotidases upon heterologous expression in Escherichia coli. They form ring complexes, which are stable after solubilization in a mild detergent and whose formation is dependent on the presence of the N-terminal extensions.
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PMID:Two unique membrane-bound AAA proteins from Sulfolobus solfataricus. 1914 14


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