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Showing PubMed Articles 1–25 of 538 from The Biochemical journal
We describe new signalling consequences for PPIP5K1-mediated phosphorylation of InsP6 and 5-InsP7 to 1-InsP7 and InsP8. In NIH-3T3 cells, either hyperosmotic stress or receptor-activation by PDGF promoted translocation of PPIP5K1 from the cytoplasm to the plasma membrane. The PtdIns(3,4,5)P3-binding domain (PBD) in PPIP5K1 recapitulated that translocation. Mutagenesis of PBD to reduce affinity for PtdIns(3,4,5)P3 prevented translocation. Using surface plasmon resonance, we found that PBD association with ve...
The misfolding and aggregation of specific proteins is a common hallmark of many neurodegenerative disorders, including highly prevalent illnesses such as Alzheimer's and Parkinson's diseases, as well as rarer disorders such as Huntington's and prion diseases. Among these, only prion diseases are 'infectious'. By seeding misfolding of the PrPC (normal conformer prion protein) into PrPSc (abnormal disease-specific conformation of prion protein), prions spread from the periphery of the body to the central ner...
Metabolic plasticity for isoprenoid biosynthesis in bacteria.
Isoprenoids are a large family of compounds synthesized by all free-living organisms. In most bacteria, the common precursors of all isoprenoids are produced by the MEP (methylerythritol 4-phosphate) pathway. The MEP pathway is absent from archaea, fungi and animals (including humans), which synthesize their isoprenoid precursors using the completely unrelated MVA (mevalonate) pathway. Because the MEP pathway is essential in most bacterial pathogens (as well as in the malaria parasites), it has been propose...
IκB kinase β (IKKβ) does not mediate feedback inhibition of the insulin signalling cascade.
STIM1 negatively regulates Ca2+ release from the sarcoplasmic reticulum in skeletal myotubes.
Stromal interaction molecule 1 (STIM1) mediates store-operated Ca2+ entry (SOCE) in skeletal muscle. However, the direct role(s) of STIM1 in skeletal muscle, such as Ca2+ release from the sarcoplasmic reticulum (SR) for muscle contraction, have not been identified. The times required for the maximal expression of endogenous STIM1 or Orai1, or for the appearance of puncta during the differentiation of mouse primary skeletal myoblasts to myotubes, were all different, and the formation of puncta was detected w...
Pivotal role of P450-P450 interactions in CYP3A4 allostery: the case of α-Naphthoflavone.
We investigated the relationship between oligomerization of cytochrome P450 3A4 (CYP3A4) and its response to alpha-naphthoflavone (ANF), a prototypical heterotropic activator. Addition of ANF resulted in over a two-fold increase in the rate of CYP3A4-dependent debenzylation of 7-benzyloxy-4-(trifluoromethyl)coumarin (7-BFC) in human liver microsomes (HLM) but failed to produce activation in BD Supersomes™ or Baculosomes® containing recombinant CYP3A4 and NADPH-cytochrome P450 reductase (CPR). However, in...
The N-terminal region of two-pore channel 1 regulates trafficking and activation by NAADP.
Two-pore channels (TPCs) are NAADP-sensitive Ca2+-permeable ion channels expressed on acidic organelles. Here we show that deletion of the N-terminal region redirects TPC1 to the ER. Introduction of fluorophores at the N-terminus of TPC1 did not affect sub-cellular location but reversibly abolishes NAADP sensitivity. Our data reveal a dual role for the N-terminus in localization and function of TPC1.
MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein.
The MondoA:Mlx transcription complex plays a pivotal role in glucose homeostasis by activating target gene expression in response to glucose-6-phosphate (G6P), the first reaction intermediate in glycolysis. Thioredoxin-interacting protein (TXNIP) is a direct and glucose-responsive target of MondoA that triggers a negative feedback loop by restricting glucose uptake when G6P levels increase. We show here that TXNIP expression is also activated by 5-aminoimidazole-4-carboxamide ribofuranoside (AICAR) and aden...
Multilevel functional and structural defects induced by two pathogenic mitochondrial tRNA mutations.
Point mutations in human mitochondrial tRNAs (hmtRNAs) can cause various disorders such as chronic progressive external ophthalmoplegia (CPEO) and mitochondrial myopathy (MM). Mitochondrial tRNALeu , especially UUR isoacceptor is recognised as a hot spot for pathogenic mitochondrial DNA point mutations. Thus far, 40 mutations have been identified in hmtRNAsLeu. Here, we describe the wide range of impacts of two substitutions found in the TΨC-arms of two hmtRNAsLeu isoacceptors. The G52A substitution, corre...
Identification of the SV2-Protein Receptor Binding Site of Botulinum Neurotoxin Type E.
The highly specific binding and uptake of botulinum neurotoxins (BoNT/A-G) into peripheral cholinergic motoneurons turns them into the most poisonous substances known. Interaction with gangliosides accumulates the neurotoxins on the plasma membrane and binding to a synaptic vesicle membrane protein leads to neurotoxin endocytosis. The synaptic vesicle (glyco-)protein 2 (SV2) mediates the uptake of BoNT/A and E, whereas synaptotagmin (Syt) is responsible for the endocytosis of BoNT/B and G. The Syt-binding s...
Mechanistic insights into small RNA recognition and modification by the HEN1 methyltransferase.
The HEN1 methyltransferase from Arabidopsis thaliana modifies the 3'-terminal nucleotides of small regulatory RNAs. Although it is one of the best characterized members of the 2'-O-methyltransferase family, many aspects of its interactions with the cofactor and substrate RNA remained unresolved. To better understand substrate interactions and contributions of individual steps during HEN1 catalysis, we studied binding and methylation kinetics using series of unmethylated, hemimethylated and doubly methylated...
The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain.
The plant cytotoxin ricin enters mammalian cells by receptor-mediated endocytosis, undergoing retrograde transport to the endoplasmic reticulum (ER) where its catalytic A chain (RTA) is reductively separated from the holotoxin to enter the cytosol and inactivate ribosomes. The currently accepted model is that the bulk of ER-dislocated RTA is degraded by proteasomes. We show here that the proteasome has a more complex role in ricin intoxication than previously recognised, that the previously reported increas...
Decreased translation of Dio3 mRNA is associated with drug-induced hepatotoxicity.
Recent work has demonstrated the importance of post-transcriptional gene regulation in toxic responses. Here we used two rat models to investigate mRNA translation in the liver following xenobiotic-induced toxicity. By combining polysome profiling with genomic methodologies we were able to assess global changes in hepatic mRNA translation. Iodothyronine deiodinase, type III (Dio3) was identified as a gene that exhibited specific translational repression and had a functional role in a number of relevant cano...
SUMOylation is a regulator of the translocation of Jak2 between nucleus and cytosol.
Jak2 initiates the signal transduction of many cytokine receptors. We discovered that Jak2 is SUMOylated on multiple lysine residues by SUMO2/3 chains. Analysis of Jak2 mutants revealed that Jak2 SUMOylation depends on the presence of an active catalytic site. We used the growth hormone receptor to study the physiological relevance of Jak2 SUMOylation. Both GH stimulation and several other environmental stressors increased Jak2 SUMOylation. Cell fractionation showed that SUMOylated Jak2 is mainly present in...
Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors.
The majority of human cancers harbour mutations promoting activation of the Akt protein kinase and Akt inhibitors are being evaluated in clinical trials. An important question concerns understanding the innate mechanisms that confer resistance of tumour cells to Akt inhibitors. The Serum and Glucocorticoid regulated Kinase (SGK) is closely related to Akt and controlled by identical upstream regulators (PI 3- kinase, PDK1 and mTORC2). Mutations that trigger activation of Akt would also stimulate SGK. Moreove...
The cell cycle and pluripotency.
PSCs (pluripotent stem cells) possess two key properties that have made them the focus of global research efforts in regenerative medicine: they have unlimited expansion potential under conditions which favour their preservation as PSCs and they have the ability to generate all somatic cell types upon differentiation (pluripotency). Conditions have been defined in vitro in which pluripotency is maintained, or else differentiation is favoured and is directed towards specific somatic cell types. However, an...
Both Met (methionine) and SAM (S-adenosylmethionine), the activated form of Met, participate in a number of essential metabolic pathways in plants. The subcellular compartmentalization of Met fluxes will be discussed in the present review with respect to regulation and communication with the sulfur assimilation pathway, the network of the aspartate-derived amino acids and the demand for production of SAM. SAM enters the ethylene, nicotianamine and polyamine biosynthetic pathways and provides the methyl grou...
With an antibody whose duty's double, a step towards ending asthma trouble?
Asthma is a debilitating chronic inflammatory disease of the airways that results in shortness of breath, wheezing and coughing, often triggered by inhalation of common allergens. The prevalence and severity of asthma has increased dramatically over the last several decades to the point where several hundred million people worldwide are affected and each year tens of thousands of individuals die prematurely from asthma symptoms. The rise in disease prevalence is particularly evident in the developed world,...
ALKBH1 is a mammalian AlkB homolog that possesses abasic site (AP) lyase activity. The AP lyase reaction is catalyzed by imine formation with an active site Lys, and a covalent intermediate can be trapped in the presence of NaBH4. Surprisingly, ALKBH1 also forms a stable protein-DNA adduct in the absence of a reducing agent. Experiments with different substrates demonstrated that the protein covalently binds to the 5' DNA product; i.e., the fragment containing an α,β-unsaturated aldehyde. The amino termin...
TMEM16A and TMEM16B proteins are Ca2+ activated Cl- channels (CaCCs) with eight putative transmembrane segments. As shown previously, expression of TMEM16B generates CaCCs characterized by a ten-fold lower Ca2+ affinity and by faster activation and deactivation kinetics with respect to TMEM16A. To investigate the basis of the different properties, we generated chimeric proteins in which different domains of the TMEM16A protein were replaced by equivalent domains of TMEM16B. Replacement of the N-terminus, tr...
Sts-1 and Sts-2 are histidine phosphatases that negatively regulate TCR signaling pathways, including those involved in cytokine production. Histidine phosphatases (HPs) play key roles in such varied biological processes as metabolism, development, and intracellular signaling. They differ considerably in primary sequence and substrate specificity, but possess a catalytic core formed by an invariant quartet of active site residues. Two histidines and two arginines cluster together within the HP active site a...
Ube2W conjugates ubiquitin to α-amino groups of protein N-termini.
The covalent attachment of the protein ubiquitin to intracellular proteins by a process known as ubiquitylation regulates almost all major cellular systems, predominantly by regulating protein turnover. Ubiquitylation requires the coordinated action of three enzymes termed E1, E2 and E3, and typically results in the formation of an isopeptide bond between the C-terminal carboxyl group of ubiquitin and the ε-amino group of a target lysine. However, ubiquitin is also known to conjugate to the sulphydryl of c...
