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At least 343 records · Page 19Linked to original sources
PubMed2004

On the molecular basis of the receptor mosaic hypothesis of the engram.

1. This paper revisits the so-called "receptor mosaic hypothesis" for memory trace formation in the light of recent findings in "functional (or interaction) proteomics." The receptor mosaic hypothesis maintains that receptors may form molecular aggregates at the plasma membrane level representing part of the computational molecular networks. 2. Specific interactions between receptors occur as a consequence of the pattern of transmitter release from the source neurons, which release the chemical code impinging on the receptor mosaics of the target neuron. Thus, the decoding of the chemical message depends on the receptors forming the receptor mosaics and on the type of interactions among receptors and other proteins in the molecular network with novel long-term mosaics formed by their stabilization via adapter proteins formed in target neurons through the incoming neurotransmitter code. The internalized receptor heteromeric complexes or parts of them may act as transcription factors for the formation of such adapter proteins. 3. Receptor mosaics are formed both at the pre- and postsynaptic level of the plasma membranes and this phenomenon can play a role in the Hebbian behavior of some synaptic contacts. The appropriate "matching" of the pre- with the postsynaptic receptor mosaic can be thought of as the "clamping of the synapse to the external teaching signal." According to our hypothesis the behavior of the molecular networks at plasma membrane level to which the receptor mosaics belong can be set in a "frozen" conformation (i.e. in a frozen functional state) and this may represent a mechanism to maintain constant the input to a neuron. 4. Thus, we are suggesting that molecular networks at plasma membrane level may display multiple "attractors" each of which stores the memory of a specific neurotransmitter code due to a unique firing pattern. Hence, this mechanism may play a role in learning processes where the input to a neuron is likely to remain constant for a while.

Animals↗
PubMed2005

Detection of human betaV-tubulin expression in epithelial cancer cell lines by tubulin proteomics.

Tubulin, the constitutive protein of microtubules, is a heterodimeric protein with an alpha and beta subunit, encoded in vertebrates by six and seven different genes, respectively. Each tubulin isotype can be identified by its divergent C-terminal sequence. Nevertheless, two groups of beta-tubulin isotypes can be distinguished by sequence alignment; one includes betaI-, betaII-, betaIVa-, and betaIVb-tubulin, and the other includes betaIII-, betaV-, and betaVI-tubulin. betaIII-tubulin overexpression has been associated with microtubule destabilization and resistance to Taxol. Recent data indicate that mouse betaV-tubulin overexpression in CHO cells results in profound microtubule disorganization and dependence of cells on Taxol for growth. Mouse and human betaV-tubulin sequences display several differences, such as their respective extreme C-terminus, suggesting that they may have different effects on microtubule stability and different affinities for drugs. When high-resolution isoelectric focusing, in-gel CNBr cleavage, and mass spectrometry were combined, we detected for the first time the betaV-tubulin protein in human cell lines and found that it was highly expressed in Hey, an epithelial ovarian cancer cell line. Our data confirm that human and rodent betaV-tubulins are distinct and indicate that, regardless of species, betaIII- and betaV-tubulin may be expressed in a complementary pattern at the protein level. Therefore, both betaIII- and betaV-tubulin expression levels should be systematically determined to assess the role of differential tubulin isotype expression in the response of tumors to drugs targeting microtubules.

Amino Acid Sequence↗
PubMed2000

Single allele knock-out of Candida albicans CGT1 leads to unexpected resistance to hygromycin B and elevated temperature.

Almost all eukaryotic mRNAs are capped at their 5'-terminus. Capping is crucial for stability, processing, nuclear export and efficient translation of mRNA. We studied the phenotypic effects elicited by depleting a Candida albicans strain of mRNA 5'-guanylyltransferase (mRNA capping enzyme; CGT1). Construction of a Cgt1-deficient mutant was achieved by URA-blaster-mediated genetic disruption of one allele of the CGT1 gene, which was localized on chromosome III. The resulting heterozygous mutant exhibited an aberrant colony morphology resembling the 'irregular wrinkle' phenotype typically obtained from a normal C. albicans strain upon mild UV treatment. Its level of CGT1 mRNA was reduced two- to fivefold compared to the parental strain. Proteome analysis revealed a large number of differentially expressed proteins confirming the expected pleiotropic effect of CGT1 disruption. The disrupted strain was significantly more resistant to hygromycin B, an antibiotic which decreases translational fidelity, and showed increased resistance to heat stress. Proteome analysis revealed a 50-fold overexpression of Ef-1alphap and a more than sevenfold overexpression of the cell-wall heat-shock protein Ssa2p. Compared to a reference strain, the cgt1/CGT1 heterozygote was equally virulent for mice and guinea pigs when tested in an intravenous infection model of disseminated candidiasis.

Alleles↗
PubMed2006

On the attenuation and amplification of molecular noise in genetic regulatory networks.

BACKGROUND: Noise has many important roles in cellular genetic regulatory functions at the nanomolar scale. At present, no good theory exists for identifying all possible mechanisms of genetic regulatory networks to attenuate the molecular noise to achieve regulatory ability or to amplify the molecular noise to randomize outcomes to the advantage of diversity. Therefore, the noise filtering of genetic regulatory network is an important topic for gene networks under intrinsic fluctuation and extrinsic noise. RESULTS: Based on stochastic dynamic regulation equation, the intrinsic fluctuation in reaction rates is modeled as a state-dependent stochastic process, which will influence the stability of gene regulatory network, especially, with low concentrations of reacting species. Then the mechanisms of genetic regulatory network to attenuate or amplify extrinsic fluctuation are revealed from the nonlinear stochastic filtering point of view. Furthermore, a simple measure of attenuation level or amplification level of extrinsic noise for genetic regulatory networks is also introduced by nonlinear robust filtering method. Based on the global linearization scheme, a convenient method is introduced to measure noise attenuation or amplification for each gene of the nonlinear stochastic regulatory network by solving a set of filtering problems, which correspond to a set of linearized stochastic regulatory networks. Finally, by the proposed methods, several simulation examples of genetic regulatory networks are given to measure their robust stability under intrinsic fluctuations, and to estimate the genes' attenuation and amplification levels under extrinsic noises. CONCLUSION: In this study, a stochastic nonlinear dynamic model is developed for genetic regulatory networks under intrinsic fluctuation and extrinsic noise. By the method we proposed, we could determine the robust stability under intrinsic fluctuations and identify the genes that are significantly affected by extrinsic noises, which we call the weak structure of the network. This method will be potential for robust gene circuit design in future, on which a drug design could be based.

Animals↗
PubMed2006

RNA editing in Drosophila melanogaster: New targets and functional consequences.

Adenosine deaminases that act on RNA [adenosine deaminase, RNA specific (ADAR)] catalyze the site-specific conversion of adenosine to inosine in primary mRNA transcripts. These re-coding events affect coding potential, splice sites, and stability of mature mRNAs. ADAR is an essential gene, and studies in mouse, Caenorhabditis elegans, and Drosophila suggest that its primary function is to modify adult behavior by altering signaling components in the nervous system. By comparing the sequence of isogenic cDNAs to genomic DNA, we have identified and experimentally verified 27 new targets of Drosophila ADAR. Our analyses led us to identify new classes of genes whose transcripts are targets of ADAR, including components of the actin cytoskeleton and genes involved in ion homeostasis and signal transduction. Our results indicate that editing in Drosophila increases the diversity of the proteome, and does so in a manner that has direct functional consequences on protein function.

Adenosine Deaminase↗
PubMed2012

Loss of CCDC6, the first identified RET partner gene, affects pH2AX S139 levels and accelerates mitotic entry upon DNA damage.

CCDC6 was originally identified in chimeric genes caused by chromosomal translocation involving the RET proto-oncogene in some thryoid tumors mostly upon ionizing radiation exposure. Recognised as a pro-apoptotic phosphoprotein that negatively regulates CREB1-dependent transcription, CCDC6 is an ATM substrate that is responsive to genotoxic stress. Here we report that following genotoxic stress, loss or inactivation of CCDC6 in cancers that carry the CCDC6 fusion, accelerates the dephosphorylation of pH2AX S139, resulting in defective G2 arrest and premature mitotic entry. Moreover, we show that CCDC6 depleted cells appear to repair DNA damaged in a shorter time compared to controls, based on reporter assays in cells. High-troughput proteomic screening predicted the interaction between the CCDC6 gene product and the catalytic subunit of Serin-Threonin Protein Phosphatase 4 (PP4c) recently identified as the evolutionarily conserved pH2AX S139 phosphatase that is activated upon DNA Damage. We describe the interaction between CCDC6 and PP4c and we report the modulation of PP4c enzymatic activity in CCDC6 depleted cells. We discuss the functional significance of CCDC6-PP4c interactions and hypothesize that CCDC6 may act in the DNA Damage Response by negatively modulating PP4c activity. Overall, our data suggest that in primary tumours the loss of CCDC6 function could influence genome stability and thereby contribute to carcinogenesis.

Cell Line↗
PubMed2005

Structural genomics analysis of alternative splicing and application to isoform structure modeling.

Alternative splicing is a sophisticated nuclear process that regulates gene expression. It represents an important mechanism for enhancing the functional diversity of proteins. Our current knowledge of alternatively spliced variants is derived mainly from mRNA transcripts, and very little is known about their protein tertiary structures. We carried out a large-scale analysis of known alternatively spliced variants at both protein sequence and structure levels and have shown that threading is, in general, a viable approach for modeling structures of alternatively spliced variants. An examination of alternative splicing at the protein sequence level revealed that the size of splicing events follows the power law distribution and the majority of splicing isoforms harbor only one or two alternations. We examined alternative splicing in the context of protein 3D structures and found that the boundaries of alternative splicing events generally happen in coil regions of secondary structures and exposed residues and the majority of the sequences involved in splicing are located on the surface of proteins. In light of these findings, we then proceeded to demonstrate that threading represents a useful tool for structure prediction of alternative splicing isoforms and addressed the fold stability issue of threading-based structure prediction by molecular dynamics simulation. Our analysis and the insights gained have helped to establish a viable method for structure prediction of alternatively spliced isoforms at the genome scale.

Alternative Splicing↗
PubMed2005

Production of constitutively acetylated recombinant p53 from yeast and Escherichia coli by tethered catalysis.

Post-translational modification of proteins is a dynamic way of generating new protein-protein interaction interfaces that are critical for signaling networks in diverse cellular functions. Purified recombinant proteins frequently lack these signature modifications. Using the tumor suppressor p53 as the model protein, we present here a tethered catalysis approach for the production of acetylated p53 in vivo. P53 is a major tumor suppressor protein that protects the cell from various oncogenic stresses. Upon DNA damage, p53 is stabilized and activated by a plethora of post-translational modifications, including acetylation. Here, we show that constitutively acetylated p53 can be expressed and purified from both yeast and Escherichia coli. This method is highly suitable for studying protein-protein interactions in the conventional yeast two-hybrid screen that requires a constitutively acetylated state of p53. Furthermore, effective production and purification of acetylated p53 from E. coli supports future biochemical and structural characterization. The method described in this work can be applied to other proteins and modifications, and thus has widespread use in the fields of signal transduction and proteomic research.

Acetylation↗
PubMed2006

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation.

The PDZ proteins such as hDLG, hScrib and MAGIs function as the membrane-associated protein scaffolds and have been shown to interact with the high-risk human papillomavirus (HPV) E6s. In this report, we identify a Golgi-associated PDZ protein, cystic fibrosis transmembrane regulator-associated ligand (CAL) as a cellular target of HPV16 E6 by the proteomic approach. The carboxy-terminal PDZ-binding motif of HPV16 E6 specifically interacts with the PDZ domain of CAL, and the interaction enhances proteasome-mediated degradation of CAL. HPV16 E6 interacts with CAL more strongly and degrades it better than HPV18 E6 owing to the more compatible PDZ-binding motif. CAL is ubiquitinated by the E6/E6-associated protein (E6AP) complex or by E6AP alone, albeit less efficiently, which indicates that it could be a normal target of E6AP. Although it downregulates CAL at the transcript level, small interfering RNA-induced depletion of HPV16 E6 in Caski cells stabilizes CAL at the protein level, suggesting that HPV16 E6 mediates the proteasomal degradation of CAL in HPV-positive cervical cancer cells. HPV16 E6 may tightly regulate the vesicular trafficking processes by interacting with CAL, and such a modification can contribute to the development of cervical cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Mass spectrometry in the analysis of grape and wine proteins.

Wine proteins play an important role in the quality of wine, because they affect taste, clarity and stability of product. The majority of wine proteins are in the range of 20-30 kDa. Different mass spectrometry (MS) techniques have been successfully applied to study the grape and wine proteins. By liquid chromatography (LC) electrospray ionization (ESI) MS and nano-LC/MS, nine dipeptides and 80 peptides were unambiguously identified in Champagne and Sauvignon Blanc wines, respectively. Using matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) and surface-enhanced laser desorption/ionization TOF, the protein and peptide fingerprints in Chardonnay, Sauvignon Blanc and Muscat of Alexandria wines were determined. MALDI-TOF identified the mesocarp proteome of six Vitis grape varieties. Proteins in different grape tissue extracts were also studied. The major grape pathogenic-related proteins are chitinases and thaumatin-like proteins, which both persist through the vinification process and cause hazes and sediments in bottled wines. ESI-MS, LC/ESI-MS and MALDI-TOF analysis of these proteins in grape and wine were also used to characterize different grape varieties.

Food Industry↗
PubMed2004

Statistical exploration of variation in quantitative two-dimensional gel electrophoresis data.

Two-dimensional gel electrophoresis is a major technique in global analysis at the protein level. This paper presents an examination of spot volume data from three gel sets with radioactively labeled yeast Saccharomyces cerevisiae proteins. A strong variance versus mean dependence in data was found to be stabilized by applying a shifted logarithmic transformation. However, transformed data showed a remaining substantial variance heterogeneity for different proteins. Furthermore, examination of studentized residuals revealed that transformed data were approximately normally distributed and that there were spatial correlations among the measurement errors in the gel.

Analysis of Variance↗
PubMed2024

Super Enhanced Purification of Denatured-Refolded Ubiquitinated Proteins by ThUBD Revealed Ubiquitinome Dysfunction in Liver Fibrosis.

Ubiquitination is crucial for maintaining protein homeostasis and plays a vital role in diverse biological processes. Ubiquitinome profiling and quantification are of great scientific significance. Artificial ubiquitin-binding domains (UBDs) have been widely employed to capture ubiquitinated proteins. The success of this enrichment relies on recognizing native spatial structures of ubiquitin and ubiquitin chains by UBDs under native conditions. However, the use of native lysis conditions presents significant challenges, including insufficient protein extraction, heightened activity of deubiquitinating enzymes and proteasomes in removing the ubiquitin signal, and purification of a substantial number of contaminant proteins, all of which undermine the robustness and reproducibility of ubiquitinomics. In this study, we introduced a novel approach that combines denatured-refolded ubiquitinated sample preparation (DRUSP) with a tandem hybrid UBD for ubiquitinomic analysis. The samples were effectively extracted using strongly denatured buffers and subsequently refolded using filters. DRUSP yielded a significantly stronger ubiquitin signal, nearly three times greater than that of the Control method. Then, eight types of ubiquitin chains were quickly and accurately restored; therefore, they were recognized and enriched by tandem hybrid UBD with high efficiency and no biases. Compared with the Control method, DRUSP showed extremely high efficiency in enriching ubiquitinated proteins, improving overall ubiquitin signal enrichment by approximately 10-fold. Moreover, when combined with ubiquitin chain-specific UBDs, DRUSP had also been proven to be a versatile approach. This new method significantly enhanced the stability and reproducibility of ubiquitinomics research. Finally, DRUSP was successfully applied to deep ubiquitinome profiling of early mouse liver fibrosis with increased accuracy, revealing novel insights for liver fibrosis research.

Animals↗
PubMed2005

The amazing complexity of transcription factories.

Multicellular eukaryotes orchestrate immensely complex patterns of gene expression in order to define numerous specialised cell types. Patterns of expression are regulated at the level of DNA modification, chromatin structure, genome architecture and nuclear organisation. Each aspect of these features of regulation is controlled by complex nuclear systems, and each of the systems must interact to define a coherent regulatory network. In proliferating cells, and particularly during development, patterns of gene expression must be preserved in cells that have active DNA repair mechanisms and efficiently duplicate both DNA and the associated chromatin status--the histone code. The systems that regulate DNA synthesis and genome stability are integrated with those that regulate the efficacy of RNA synthesis, such that patterns of gene expression are maintained. This review analyses how different experimental approaches are revealing the amazing complexity of the transcriptionally active compartment of mammalian cells. The functional implications of this complexity will be discussed.

Animals↗
PubMed2006

Enrichment of carbonylated peptides using Girard P reagent and strong cation exchange chromatography.

It has been shown that oxidatively modified forms of proteins accumulate during oxidative stress, aging, and in some age-related diseases. One of the unique features of protein oxidation by a wide variety of routes is the generation of carbonyl groups. Of major interest in the study of oxidative stress diseases is which proteins in a proteome are being oxidized and the site(s) of oxidation. Based on the fact that proteins are generally characterized through tryptic peptide fragments, this paper reports a method for the isolation of oxidized peptides, which involves (1) derivatization of oxidized proteins with Girard P reagent (GRP; 1-(2-hydrazino-2-oxoethyl)pyridinium chloride), (2) following proteolysis enrichment of the derivatized peptide using strong cation exchange (SCX) chromatography, and (3) identification of oxidation sites using tandem mass spectrometry. Derivatization of aldehydes and ketones in oxidized proteins was accomplished by reacting protein carbonyls with the hydrazide of GRP. The resulting hydrazone bond was reduced by sodium cyanoborohydride to further stabilize the labeling. Derivatization time and concentrations of the derivatizing agent were optimized with model peptides. Oxidized transferrin was used as model protein to study derivatization efficiency at the protein level. Following metal-catalyzed oxidation of transferrin, the protein was derivatized with GRP and trypsin digested. Positively charged peptides were then selected from the digest with SCX chromatography at pH 6.0. Seven GRP-derivatized peptides were found to be selected from transferrin by MALDI-TOF-TOF analysis. Fourteen underivatized native peptides were also captured by the SCX column at pH 6.0. Mapping of the derivatized peptides onto the primary structure of transferrin indicated that the oxidation sites were all on solvent-accessible regions at the protein surface. Efficiency of the method was further demonstrated in the identification of oxidized proteins from yeast.

Binding Sites↗
PubMed2004

Silencing of SPC2 expression using an engineered delta ribozyme in the mouse betaTC-3 endocrine cell line.

Endoproteolytic processing is carried out by subtilase-like pro-protein convertases in mammalian cells. In order to understand the distinct roles of a member of this family (SPC2), gene silencing in cultured cells is an ideal approach. Previous studies showed limited success in either the degree of inhibition obtained or the stability of the cell lines. Here we demonstrate the high potential of delta ribozyme as a post-transcriptional gene silencing tool in cultured cells. We used an expression vector based on the RNA polymerase III promoter to establish betaTC-3 stable cell lines expressing the chimeric tRNA(Val)-delta ribozyme transcript targeting SPC2 mRNA. Northern and Western blot hybridizations showed a specific reduction of SPC2 mRNA and protein. Validation of processing effects was tested by measuring the levels of dynorphin A-(1-8), which are present in betaTC-3 cells as a result of the unique cleavage of dynorphin A-(1-17) by SPC2. Moreover, a differential proteomic analysis confirmed these results and allowed identification of secretogranin II as a potential substrate of SPC2. The development of efficient, specific, and durable silencing tools, such as described in the present work, will be of great importance in elucidating the functions of the subtilase-like pro-protein convertases in regard to peptide processing and derived cellular events.

Animals↗
PubMed2005

Proximity-induced catalysis by the protein kinase ERK2.

Five hundred protein kinases phosphorylate 10 000 proteins in human cells. Frequently, more than one site in a protein is phosphorylated, and often by more than one protein kinase. The mechanistic basis underlying the overlapping specificity of the phospho-proteome is not well understood. We are interested in understanding why ERK2, a proline-directed protein kinase, phosphorylates only a fraction of the (S/T-P) sites found in the surface loops of proteins, at an appreciable rate. To address this fundamental question, we utilized a well-established protein substrate EtsDelta138, which comprises a globular ERK2-recognition domain (pnt domain) and an unstructured peptide-like N-terminal tail. This tail contains T38, the sole ERK2 phosphorylation site. We mutated the TP motif, which is recognized by the active site and found that mutagenesis of the T-38/P-39 motif to TD, TR, TA, TG, and TV has no effect on the stability of the ternary complex but does decrease kcat. We also investigated the effect of perturbing the binding between ERK2 and the pnt domain, which occurs outside the active site, to find that mutation of the pnt domain (F120A) leads to a 10-fold decrease in binding but the kcat remains the same. The data support a mechanism of proximity-mediated catalysis, where the docking of the pnt domain, outside the active site, increases the effective concentration of the TP motif near the active site. The data are consistent with the notion that the interaction between ERK2 and the pnt domain provides uniform binding energy and stabilizes each enzyme intermediate and transition state to an equal extent. While other steps on the reaction pathway contribute towards the specificity of the ERK2 reaction, a docking interaction provides the initial basis for substrate recognition. Those residues within the docked complex, which have the ability to access the active site with an appropriate geometry, can be phosphorylated at an efficient rate if followed by a proline or small hydrophobic amino acid.

Animals↗
PubMed2006

Genomic and evolutionary insights into genes encoding proteins with single amino acid repeats.

Mutations causing expansion of amino acid repeats are responsible for 19 hereditary disorders. Repeats in several other proteins also show length variations. These observations prompted us to identify single amino acid repeat-containing proteins (SARPs) in humans and to understand their functional and evolutionary significance. We identified 8812 SARPs containing 17 146 repeat domains, each harboring 4 or more residues. In all, 5% of SARPs (471) showed repeat length variations, and nearly 84% of them (394) have repeats of 10 residues or less. We find that SARPs are involved in functions that require formation of multiprotein complexes. Nearly 78% (6859) of the SARPs did not find a paralogue in the human proteome, and such proteins are considered as orphan SARPs. Orphan SARPs show longer repeat stretches, longer peptide length, and lower expression levels as compared with SARPs belonging to protein family. Because the intensity of gene expression is known to relate inversely with the rate of protein sequence evolution, our results suggest that the orphan SARPs evolve faster than the familial forms and therefore are under a weaker selection pressure. We also find that while GC-rich codons are favored for coding the repeat tracts of SARPs, specific codons and not nucleotide motifs per se are selected, suggesting functional constraints placed on the usage of codons. One of the constraints could be the mRNA stability as clustering of rare codons is known to destabilize the transcripts and rare codons are not favored for coding repeat tracts. Genes encoding polymorphic SARPs show preferential localization toward the telomeric segments. Further, the sex-specific recombination rates of the chromosomal locus strongly correlate with the parental gender that influence the repeat instability in disorder caused by dynamic mutation. Therefore, instability associated with repeats might be driven by processes that are specific to sperm or oocyte development, and the recombination frequency might play a positive role in this process.

Base Sequence↗
PubMed2007

Ligand-controlled proteolysis of the Escherichia coli transcriptional regulator ZntR.

Proteases play a crucial role in remodeling the bacterial proteome in response to changes in cellular environment. Escherichia coli ZntR, a zinc-responsive transcriptional regulator, was identified by proteomic experiments as a likely ClpXP substrate, suggesting that protein turnover may play a role in regulation of zinc homeostasis. When intracellular zinc levels are high, ZntR activates expression of ZntA, an ATPase essential for zinc export. We find that ZntR is degraded in vivo in a manner dependent on both the ClpXP and Lon proteases. However, ZntR degradation decreases in the presence of high zinc concentrations, the level of ZntR rises, and transcription of the zntA exporter is increased. Mutagenesis experiments reveal that zinc binding does not appear to be solely responsible for the zinc-induced protection from proteolysis. Therefore, we tested whether DNA binding was important in the zinc-induced stabilization of ZntR by mutagenesis of the DNA binding helices. Replacement of a conserved arginine (R19A) in the DNA binding domain both enhances ZntR degradation and abolishes zinc-induced transcriptional activation of zntA. Biochemical and physical analysis of ZntR(R19A) demonstrates that it is structurally similar to, and binds zinc as well as does, the wild-type protein but is severely defective in binding DNA. Thus, we conclude that two different ligands-zinc and DNA-function together to increase ZntR stability and that ligand-controlled proteolysis of ZntR plays an important role in fine-tuning zinc homeostasis in bacteria.

ATPases Associated with Diverse Cellular Activitie↗