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)

Misfolded proteins of the endoplasmic reticulum (ER) are discarded by a conserved process, called ER-associated protein degradation (ERAD). ERAD substrates are retro-translocated into the cytosol, polyubiquitinated, extracted from the ER membrane, and ultimately degraded by the proteasome. Recent in vitro experiments with purified components have given insight into the mechanism of ERAD. ERAD substrates with misfolded luminal or intramembrane domains are moved across the ER membrane through a channel formed by the multispanning ubiquitin ligase Hrd1. Following polyubiquitination, substrates are extracted from the membrane by the Cdc48/p97 ATPase complex and transferred to the proteasome. We discuss the molecular mechanism of these processes and point out remaining open questions.
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PMID:Mechanistic insights into ER-associated protein degradation. 2971 69

The compatible microbial consortia containing fungal and bacterial symbionts acting synergistically are applied to improve plant growth and eco-physiological responses in extreme crop growth conditions. However, the interactive effects of phytohormones-producing endophytic fungal and bacterial symbionts plant growth and stress tolerance under heavy metal stress have been least known. In the current study, the phytohormones-producing endophytic Paecilomyces formosus LHL10 and Sphingomonas sp. LK11 revealed potent growth and tolerance during their initial screening against combined Al and Zn (2.5 mM each) stress. This was followed with their co-inoculation in the Al- and Zn-stressed Glycine max L. plants, showing significantly higher plant growth attributes (shoot/root length, fresh/dry weight, and chlorophyll content) than the plants solely inoculated with LHL10 or LK11 and the non-inoculated (control) plants under metal stresses. Interestingly, under metal stress, the consortia exhibited lower metal uptake and inhibited metal transport in roots. Metal-induced oxidative stresses were modulated in co-inoculated plants through reduced hydrogen peroxide, lipid peroxidation, and antioxidant enzymes (catalase and superoxide dismutase) in comparison to the non-inoculated plants. In addition, endophytic co-inoculation enhanced plant macronutrient uptake (P, K, S, and N) and modulated soil enzymatic activities under stress conditions. It significantly downregulated the expression of heavy metal ATPase genes GmHMA13, GmHMA18, GmHMA19, and GmPHA1 and upregulated the expression of an ariadne-like ubiquitin ligase gene GmARI1 under heavy metals stress. Furthermore, the endogenous phytohormonal contents of co-inoculated plants revealed significantly enhanced gibberellins and reduced abscisic acid and jasmonic acid contents, suggesting that this endophytic interaction mitigated the adverse effect of metal stresses in host plants. In conclusion, the co-inoculation of the endophytic fungus LHL10 and bacteria LK11 actively contributed to the tripartite mutualistic symbiosis in G. max under heavy metal stresses; this could be used an excellent strategy for sustainable agriculture in the heavy metal-contaminated fields.
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PMID:Endophytic Microbial Consortia of Phytohormones-Producing Fungus Paecilomyces formosus LHL10 and Bacteria Sphingomonas sp. LK11 to Glycine max L. Regulates Physio-hormonal Changes to Attenuate Aluminum and Zinc Stresses. 3023 18

The bone morphogenetic protein (BMP)-Smad signaling pathway plays a crucial role in the control of bone homeostasis by regulating osteoblast activity. It is known that the ubiquitin ligase Smad ubiquitination regulatory factor (Smurf)1 is a master negative regulator of BMP signaling, but how its stability and activity are regulated remains poorly understood. Our study showed that valosin-containing protein/p97, the mutations of which lead to rare forms of Paget's disease of bone (PDB)-like syndrome-such as inclusion body myopathy (IBM) associated with Paget's disease of bone and frontotemporal dementia (IBM-PFD)-together with its adaptor nuclear protein localization (NPL)4, specifically interact with Smurf1 and deliver the ubiquitinated Smurf1 for degradation. Depletion of either p97 or NPL4 resulted in the elevation of Smurf1 protein level and decreased BMP signaling accordingly. Mechanically, a typical proline, glutamic acid, serine, and threonine motif specifically existing in Smurf1 is necessary for its recognition and degradation by p97, and this process is dependent on p97 ATPase activity. More importantly, compared with p97 WT, PDB-associated mutation of p97 (mainly A232E) harboring the higher ATPase activity of p97 further promoted Smurf1 degradation, thus increasing BMP signaling activity. Our findings first establish a link between p97 and Smurf1, providing an in-depth understanding of how Smurf1 is regulated, as well as the mechanism of p97-related bone diseases.-Li, H., Cui, Y., Wei, J., Liu, C., Chen, Y., Cui, C.-P., Li, L., Zhang, X., Zhang, L. VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation.
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PMID:VCP/p97 increases BMP signaling by accelerating ubiquitin ligase Smurf1 degradation. 3033 48

Translational stalling of ribosome bound to endoplasmic reticulum (ER) membrane requires an accurate clearance of the associated polypeptides, which is not completely understood in mammals. We characterized in mammalian cells the model of ribosomal stalling at the STOP-codon based on proteins tagged at the C-terminus with the picornavirus 2A peptide followed by a termination codon instead of the Proline (2A*). We exploited the 2A* stalling model to characterize the pathway of degradation of ER-targeted polypeptides. We report that the ER chaperone BiP/GRP78 is a new main factor involved. Moreover, degradation of the ER-stalled polypeptides required the activities of the AAA-ATPase VCP/p97, its associated deubiquitinylase YOD1, the ribosome-associated ubiquitin ligase Listerin and the proteasome. In human proteome, we found two human C-terminal amino acid sequences that cause similar stalling at the STOP-codon. Our data suggest that translational stalling at the ER membrane activates protein degradation at the interface of ribosomal- and ER-associated quality control systems.
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PMID:BiP/GRP78 Mediates ERAD Targeting of Proteins Produced by Membrane-Bound Ribosomes Stalled at the STOP-Codon. 3050 27

The leucine zipper-like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease-associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.
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PMID:Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. 3065 96

Recent studies have revealed the feasibility of sodium acetate as a potentially novel inhibitor/stressor relevant to the fermentation from neutralized lignocellulosic hydrolysates. This mini-review focuses on the toxicity of sodium acetate, which is composed of both sodium and acetate ions, and on the involved cellular responses that it elicits, particularly via the high-osmolarity glycerol (HOG) pathway, the Rim101 pathway, the P-type ATPase sodium pumps Ena1/2/5, and the ubiquitin ligase Rsp5 with its adaptors. Increased understanding of cellular responses to sodium acetate would improve our understanding of how cells respond not only to different stimuli but also to composite stresses induced by multiple components (e.g., sodium and acetate) simultaneously. Moreover, unraveling the characteristics of specific stresses under industrially related conditions and the cellular responses evoked by these stresses would be a key factor in the industrial yeast strain engineering toward the increased productivity of not only bioethanol but also advanced biofuels and valuable chemicals that will be in demand in the coming era of bio-based industry.
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PMID:Sodium Acetate Responses in Saccharomyces cerevisiae and the Ubiquitin Ligase Rsp5. 3045 28

Mysterin, also known as RNF213, is an intracellular protein that forms large toroidal oligomers. Mysterin was originally identified in genetic studies of moyamoya disease (MMD), a rare cerebrovascular disorder of unknown etiology. While mysterin is known to exert ubiquitin ligase and putative mechanical ATPase activities with a RING finger domain and two adjacent AAA+ modules, its biological role is poorly understood. Here, we report that mysterin is targeted to lipid droplets (LDs), ubiquitous organelles specialized for neutral lipid storage, and markedly increases their abundance in cells. This effect was exerted primarily through specific elimination of adipose triglyceride lipase (ATGL) from LDs. The ubiquitin ligase and ATPase activities of mysterin were both important for its proper LD targeting. Notably, MMD-related mutations in the ubiquitin ligase domain of mysterin significantly impaired its fat-stabilizing activity. Our findings identify a unique new regulator of cytoplasmic LDs and suggest a potential link between the pathogenesis of MMD and fat metabolism.
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PMID:The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets. 3070 59

Resolution of branched DNA structures is pivotal for repair of stalled replication forks and meiotic recombination intermediates. The Yen1 nuclease cleaves both Holliday junctions and replication forks. We show that Yen1 interacts physically with Uls1, a suggested SUMO-targeted ubiquitin ligase that also contains a SWI/SNF-family ATPase-domain. Yen1 is SUMO-modified in its noncatalytic carboxyl terminus and DNA damage induces SUMOylation. SUMO-modification of Yen1 strengthens the interaction to Uls1, and mutations in SUMO interaction motifs in Uls1 weakens the interaction. However, Uls1 does not regulate the steady-state level of SUMO-modified Yen1 or chromatin-associated Yen1. In addition, SUMO-modification of Yen1 does not affect the catalytic activity in vitro. Consistent with a shared function for Uls1 and Yen1, mutations in both genes display similar phenotypes. Both uls1 and yen1 display negative genetic interactions with the alternative HJ-cleaving nuclease Mus81, manifested both in hypersensitivity to DNA damaging agents and in meiotic defects. Point mutations in ULS1 (uls1K975R and uls1C1330S, C1333S) predicted to inactivate the ATPase and ubiquitin ligase activities, respectively, are as defective as the null allele, indicating that both functions of Uls1 are essential. A micrococcal nuclease sequencing experiment showed that Uls1 had minimal effects on global nucleosome positioning/occupancy. Moreover, increased gene dosage of YEN1 partially alleviates the mus81 uls1 sensitivity to DNA damage. We suggest a preliminary model in which Uls1 acts in the same pathway as Yen1 to resolve branched DNA structures.
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PMID:Helicase/SUMO-targeted ubiquitin ligase Uls1 interacts with the Holliday junction resolvase Yen1. 3089 39

The Mad2-binding protein p31^comet has important roles in the inactivation of the mitotic checkpoint system, which delays anaphase until chromosomes attach correctly to the mitotic spindle. The activation of the checkpoint promotes the assembly of a Mitotic Checkpoint Complex (MCC), which inhibits the action of the ubiquitin ligase APC/C (Anaphase-Promoting Complex/Cyclosome) to degrade inhibitors of anaphase initiation. The inactivation of the mitotic checkpoint requires the disassembly of MCC. p31^comet promotes the disassembly of mitotic checkpoint complexes by liberating their Mad2 component in a joint action with the ATPase TRIP13. Here, we investigated the regulation of p31^comet action. The release of Mad2 from checkpoint complexes in extracts from nocodazole-arrested HeLa cells was inhibited by Polo-like kinase 1 (Plk1), as suggested by the effects of selective inhibitors of Plk1. Purified Plk1 bound to p31^comet and phosphorylated it, resulting in the suppression of its activity (with TRIP13) to disassemble checkpoint complexes. Plk1 phosphorylated p31^comet on S102, as suggested by the prevention of the phosphorylation of this residue in checkpoint extracts by the selective Plk1 inhibitor BI-2536 and by the phosphorylation of S102 with purified Plk1. An S102A mutant of p31^comet had a greatly decreased sensitivity to inhibition by Plk1 of its action to disassemble mitotic checkpoint complexes. We propose that the phosphorylation of p31^comet by Plk1 prevents a futile cycle of MCC assembly and disassembly during the active mitotic checkpoint.
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PMID:Role of Polo-like kinase 1 in the regulation of the action of p31^comet in the disassembly of mitotic checkpoint complexes. 3111 82

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease characterized by a progressive decline in motor function. Genetic analyses have identified several genes mutated in ALS patients, and one of them is Cyclin F gene (CCNF), the product of which (Cyclin F) serves as the substrate-binding module of a SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complex. However, the role of Cyclin F in ALS pathogenesis has remained unclear. Here, we show that Cyclin F binds to valosin-containing protein (VCP), which is also reported to be mutated in ALS, and that the two proteins colocalize in the nucleus. VCP was found to bind to the NH2-terminal region of Cyclin F and was not ubiquitylated by SCFCyclin F in transfected cells. Instead, the ATPase activity of VCP was enhanced by Cyclin F in vitro. Furthermore, whereas ALS-associated mutations of CCNF did not affect the stability of Cyclin F or disrupt formation of the SCFCyclin F complex, amino acid substitutions in the VCP binding region increased the binding ability of Cyclin F to VCP and activity of VCP as well as mislocalization of the protein in the cytoplasm. We also provided evidence that the ATPase activity of VCP promotes cytoplasmic aggregation of transactivation responsive region (TAR) DNA-binding protein 43, which is commonly observed in degenerating neurons in ALS patients. Given that mutations of VCP identified in ALS patients also increase its ATPase activity, our results suggest that Cyclin F mutations may contribute to ALS pathogenesis by increasing the ATPase activity of VCP in the cytoplasm, which in turn increases TDP-43 aggregates.
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PMID:Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity. 3157 44


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