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

---

Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p97/VCP is a multifunctional AAA(+)-family ATPase that is involved in diverse cellular processes. p97/VCP directly interacts with various adaptors for activity in different biochemical contexts. Among these adaptors are p47 and Fas-associated factor 1 (FAF1), which contain a common UBX domain through which they bind to the N domain of p97/VCP. In the ubiquitin-proteasome pathway, p97/VCP acts as a chaperone that presents client proteins to the proteasome for degradation, while FAF1 modulates the process by interacting with ubiquitinated client proteins and also with p97/VCP. In an effort to elucidate the structural details of the interaction between p97/VCP and FAF1, the p97/VCP N domain was crystallized in complex with the FAF1 UBX domain. X-ray data were collected to 2.60 A resolution and the crystals belonged to space group C222(1), with unit-cell parameters a = 58.24, b = 72.81, c = 132.93 A. The Matthews coefficient and solvent content were estimated to be 2.39 A(3) Da(-1) and 48.4%, respectively, assuming that the asymmetric unit contained p97/VCP N domain and FAF1 molecules in a 1:1 ratio, which was subsequently confirmed by molecular-replacement calculations.
...
PMID:Crystallization and preliminary X-ray crystallographic analysis of the N domain of p97/VCP in complex with the UBX domain of FAF1. 2005 67

VCP (VCP/p97) is a ubiquitously expressed member of the AAA(+)-ATPase family of chaperone-like proteins that regulates numerous cellular processes including chromatin decondensation, homotypic membrane fusion and ubiquitin-dependent protein degradation by the proteasome. Mutations in VCP cause a multisystem degenerative disease consisting of inclusion body myopathy, Paget disease of bone, and frontotemporal dementia (IBMPFD). Here we show that VCP is essential for autophagosome maturation. We generated cells stably expressing dual-tagged LC3 (mCherry-EGFP-LC3) which permit monitoring of autophagosome maturation. We determined that VCP deficiency by RNAi-mediated knockdown or overexpression of dominant-negative VCP results in significant accumulation of immature autophagic vesicles, some of which are abnormally large, acidified and exhibit cathepsin B activity. Furthermore, expression of disease-associated VCP mutants (R155H and A232E) also causes this autophagy defect. VCP was found to be essential to autophagosome maturation under basal conditions and in cells challenged by proteasome inhibition, but not in cells challenged by starvation, suggesting that VCP might be selectively required for autophagic degradation of ubiquitinated substrates. Indeed, a high percentage of the accumulated autophagic vesicles contain ubiquitin-positive contents, a feature that is not observed in autophagic vesicles that accumulate following starvation or treatment with Bafilomycin A. Finally, we show accumulation of numerous, large LAMP-1 and LAMP-2-positive vacuoles and accumulation of LC3-II in myoblasts derived from patients with IBMPFD. We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes and that defect in this function may contribute to IBMPFD pathogenesis.
...
PMID:VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD. 2010 22

Fas-associated factor 1 (FAF1) is a multifunctional pro-apoptotic protein that is involved in Fas-mediated apoptosis, NF-kappaB signalling and the ubiquitin-proteasome pathway. In the ubiquitin-proteasome pathway, FAF1 binds to the N domain of p97/VCP, a molecular chaperone that acts in complex with the proteasome, through its C-terminal UBX domain and inhibits the proteasomal protein-degradation process. In an effort to elucidate the structural basis of the function of FAF1 in modulating p97/VCP activity related to proteasomal protein degradation, crystallographic analysis of the FAF1 UBX domain and the p97/VCP N domain was initiated. Following the recently reported crystallization of the FAF1 UBX domain bound to the p97/VCP N domain, the unbound FAF1 UBX domain was also crystallized for purposes of structural comparison. X-ray data were collected to 3.00 A resolution and the crystals belonged to space group F4(1)32, with unit-cell parameters a = b = c = 176.40 A. The Matthews coefficient and solvent content were estimated to be 3.04 A(3) Da(-1) and 59.5%, respectively, assuming that the asymmetric unit contained two molecules of the UBX domain, which was subsequently confirmed by molecular-replacement calculations.
...
PMID:Crystallization and preliminary X-ray crystallographic analysis of human FAF1 UBX domain. 2012 26

Inclusion body myopathy associated with Paget's disease of the bone and fronto-temporal dementia (IBMPFD) is a progressive autosomal dominant disorder caused by mutations in p97/VCP (valosin-containing protein). p97/VCP is a member of the AAA+ (ATPase associated with a variety of activities) protein family and participates in multiple cellular processes. One particularly important role for p97/VCP is facilitating intracellular protein degradation. p97/VCP has traditionally been thought to mediate the ubiquitin-proteasome degradation of proteins; however, recent studies challenge this dogma. p97/VCP clearly participates in the degradation of aggregate-prone proteins, a process principally mediated by autophagy. In addition, IBMPFD mutations in p97/VCP lead to accumulation of autophagic structures in patient and transgenic animal tissue. This is likely due to a defect in p97/VCP-mediated autophagosome maturation. The following review will discuss the evidence for p97/VCP in autophagy and how a disruption in this process contributes to IBMPFD pathogenesis.
...
PMID:Inclusion body myopathy, Paget's disease of the bone and fronto-temporal dementia: a disorder of autophagy. 2041 Feb 87

The valosin-containing protein (p97) is a ubiquitin-dependent ATPase that plays central roles in ubiquitin proteasome system (UPS)-mediated protein degradation pathways. p97 has been recently identified as a putative substrate of active Caspase-6 (Casp6) in primary human neurons. Since Casp6 is activated in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients' brains, the targeting of p97 by Casp6 may represent an important step that leads to UPS impairment in AD. Here, we show that p97 is a Casp6 substrate in vitro and in vivo. Casp6 cleavage of recombinant p97 generated two N-terminal fragments of 28 and 20 kDa, which were not generated by the other two effector caspases, Caspase-3 and Caspase-7. ATP binding to the D1 ATPase ring of p97 reduced the susceptibility of the N-domain to caspase-mediated proteolysis. Mass spectrometric analysis identified VAPD(179) as a Casp6 cleavage site within p97's N-domain. An anti-neoepitope serum immunohistochemically detected p97 cleaved at VAPD(179) in the cytoplasm of the cell soma and neurites of hippocampal neurons in MCI and AD. Overexpression of p97 (1-179) fragment, representing p97 cleaved at D179, impaired the degradation of model substrates in the ubiquitin-fusion degradation and the N-end rule pathways, and destabilized endogenous p97. Collectively, these results show that p97 is cleaved by Casp6 in AD and suggest p97 cleavage as an important mechanism for UPS impairment.
...
PMID:Identification of Caspase-6-mediated processing of the valosin containing protein (p97) in Alzheimer's disease: a novel link to dysfunction in ubiquitin proteasome system-mediated protein degradation. 2042 71

Terminally misfolded proteins that accumulate in the endoplasmic reticulum (ER) are dislocated and targeted for ubiquitin-dependent destruction by the proteasome. UBC6e is a tail-anchored E2 ubiquitin-conjugating enzyme that is part of a dislocation complex nucleated by the ER-resident protein SEL1L. Little is known about the turnover of tail-anchored ER proteins. We constructed a set of UBC6e transmembrane domain replacement mutants and found that the tail anchor of UBC6e is vital for its function, its stability, and its mode of membrane integration, the last step dependent on the ASNA1/TRC40 chaperone. We constructed a tail-anchored UBC6e variant that requires for its removal from the ER membrane not only YOD1 and p97, two cytosolic proteins involved in the extraction of ER transmembrane or luminal proteins, but also UBXD8, AUP1 and members of the Derlin family. Degradation of tail-anchored proteins thus relies on components that are also used in other aspects of protein quality control in the ER.
...
PMID:The transmembrane segment of a tail-anchored protein determines its degradative fate through dislocation from the endoplasmic reticulum. 2043 96

Mouse mammary tumor virus (MMTV) is a complex murine retrovirus that encodes an HIV Rev-like export protein, Rem, from a doubly spliced version of envelope (Env) mRNA. Previously, the N-terminal 98-amino acid sequence of Rem, which is identical to Env signal peptide (SP), and full-length Rem were shown to be functional in a reporter assay that measures a postexport function. Here we show that MMTV-infected cells or cells transfected with rem or env cDNAs express SP, which is the active component in the reporter assay. Uncleaved Rem was partially glycosylated, but mutations in both glycosylation sites within the C terminus prevented Rem function. Mutations that reduced Rem or Env cleavage by signal peptidase greatly reduced SP levels and functional activity in the reporter assay and allowed accumulation of the uncleaved protein. Fluorescence microscopy revealed that GFP-tagged cleavage-site mutants are unstable and lack fluorescence compared with wild-type Rem, suggesting improper folding. Proteasome inhibitors allowed accumulation of uncleaved Rem relative to SP and increased reporter activity, consistent with SP retrotranslocation and proteasome escape before nuclear entry. Expression of a dominant-negative p97 ATPase did not alter levels of unprocessed Rem and SP but decreased reporter activity, suggesting p97-facilitated retrotranslocation of SP. Our results provide an example of a SP that is processed by signal peptidase and retrotranslocated to allow nuclear localization and function.
...
PMID:Retroviral Rem protein requires processing by signal peptidase and retrotranslocation for nuclear function. 2056 71

The endoplasmic reticulum (ER) is a major site of protein synthesis and facilitates the folding and assembly of newly synthesized proteins. Misfolded proteins are retrotranslocated across the ER membrane and destroyed at the proteasome. DERL1 is an important protein involved in the retrotranslocation and degradation of a subset of misfolded proteins from the ER. We characterized a 2617 bp cDNA from bovine granulosa cells that corresponded to bovine DERL1. Two transcripts of 3 and 2.6 kb were detected by Northern blot analysis, and showed variations in expression among tissues. During follicular development, DERL1 expression was greater in day 5 dominant follicles compared to small follicles, ovulatory follicles, or corpus luteum (CL). Within the CL, DERL1 mRNA expression was intermediate in midcycle, and lowest in late cycle as compared to early in the estrous cycle. Western blot analyses demonstrated the presence of DERL1 in the bovine CL at days 5, 11, and 18 of the estrous cycle. Co-immunoprecipitation using luteal tissues showed that DERL1 interacts with class I MHC but not with VIMP or p97 ATPase. The interaction between DERL1 and MHC I suggests that, in the CL, DERL1 may regulate the integrity of MHC I molecules that are transported to the ER membrane. Furthermore, the greater expression of DERL1 mRNA is associated with the active follicular development and early luteal stages, suggesting a role of DERL1 in tissue remodeling events and maintenance of function in reproductive tissues.
...
PMID:Molecular characterization and expression of DERL1 in bovine ovarian follicles and corpora lutea. 2068 45

The molecular details of the biogenesis of double-membraned autophagosomes are poorly understood. We identify the Saccharomyces cerevisiae AAA-adenosine triphosphatase Cdc48 and its substrate-recruiting cofactor Shp1/Ubx1 as novel components needed for autophagosome biogenesis. In mammals, the Cdc48 homologue p97/VCP and the Shp1 homologue p47 mediate Golgi reassembly by extracting an unknown monoubiquitinated fusion regulator from a complex. We find no requirement of ubiquitination or the proteasome system for autophagosome biogenesis but detect interaction of Shp1 with the ubiquitin-fold autophagy protein Atg8. Atg8 coupled to phosphatidylethanolamine (PE) is crucial for autophagosome elongation and, in vitro, mediates tethering and hemifusion. Interaction with Shp1 requires an FK motif within the N-terminal non-ubiquitin-like Atg8 domain. Based on our data, we speculate that autophagosome formation, in contrast to Golgi reassembly, requires a complex in which Atg8 functionally substitutes ubiquitin. This, for the first time, would give a rationale for use of the ubiquitin-like Atg8 during macroautophagy and would explain why Atg8-PE delipidation is necessary for efficient macroautophagy.
...
PMID:Cdc48/p97 and Shp1/p47 regulate autophagosome biogenesis in concert with ubiquitin-like Atg8. 2085 2

Coordinated regulation of the ubiquitin-proteasome system (UPS) is crucial for the cell to adjust its protein degradation capacity to changing proteolytic requirements. We have shown previously that mammalian cells upregulate proteasome gene expression in response to proteasome inhibition. Here, we report the identification of the transcription factor TCF11 (long isoform of Nrf1) as a key regulator for 26S proteasome formation in human cells to compensate for reduced proteolytic activity. Under noninducing conditions, TCF11 resides in the endoplasmic reticulum (ER) membrane. There, TCF11 is targeted to ER-associated protein degradation requiring the E3 ubiquitin ligase HRD1 and the AAA ATPase p97. Proteasome inhibitors trigger the accumulation of oxidant-damaged proteins and promote the nuclear translocation of TCF11 from the ER, permitting activation of proteasome gene expression by binding to antioxidant response elements in their promoter regions. Thus, we uncovered the transcriptional control loop regulating human proteasome-dependent protein degradation to counteract proteotoxic stress caused by proteasome inhibition.
...
PMID:Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. 2093 82


<< Previous 1 2 3 4 5 6 7 8 9 10

---