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At least 1,369 records · Page 76Linked to original sources
PubMed2005

Heterologous RNA replication enhancer stimulates in vitro RNA synthesis and template-switching by the carmovirus, but not by the tombusvirus, RNA-dependent RNA polymerase: implication for modular evolution of RNA viruses.

The viral RNA plays multiple roles during replication of RNA viruses, serving as a template for complementary RNA synthesis and facilitating the assembly of the viral replicase complex. These roles are coordinated by cis-acting regulatory elements, such as promoters and replication enhancers (REN). To test if these RNA elements can be used by related viral RNA-dependent RNA polymerases (RdRp), we compared the potential stimulatory effects of homologous and heterologous REN elements on complementary RNA synthesis and template-switching by the tombus- (Cucumber necrosis virus, CNV), carmovirus (Turnip crinkle virus, TCV) and hepatitis C virus (HCV) RdRps in vitro. The CNV RdRp selectively utilized its cognate REN, while discriminating against the heterologous TCV REN. On the contrary, RNA synthesis by the TCV RdRp was stimulated by the TCV REN and the heterologous tombusvirus REN with comparable efficiency. The heterologous REN elements also promoted in vitro template-switching by the TCV and HCV RdRps. Based on these observations, we propose that REN elements could facilitate intervirus recombination and post-recombinational amplification of new recombinant viruses.

Base Sequence↗
PubMed2005

Testing the modularity of the N-terminal amphipathic helix conserved in picornavirus 2C proteins and hepatitis C NS5A protein.

The N-terminal region of the picornaviral 2C protein is predicted to fold into an amphipathic alpha-helix that is responsible for the protein's association with membranes in the viral RNA replication complex. We have identified a similar sequence in the N-terminal region of NS5A of hepaciviruses that was recently shown to form an amphipathic alpha-helix. The conservation of the N-terminal region in two apparently unrelated proteins of two different RNA virus families suggested that this helix might represent an independent module. To test this hypothesis, we constructed chimeric poliovirus (PV) genomes in which the sequence encoding the N-terminal 2C amphipathic helix was replaced by orthologous sequences from other picornaviral genomes or a similar sequence from NS5A of HCV. Effects of the mutations were assessed by measuring the accumulation of viable virus and viral RNA in HeLa cells after transfection, examining membrane morphology in cells expressing chimeric proteins and by in vitro analysis of RNA translation, protein processing and negative strand RNA synthesis in HeLa cell extracts. The chimeras manifested a wide range of growth and RNA synthesis phenotypes. The results are compatible with our hypothesis, although they demonstrate that helix exchangeability may be restricted due to requirements for interactions with other viral components involved in virus replication.

Amino Acid Sequence↗
PubMed2005

A modular cis-regulatory system controls isoform-specific pitx expression in ascidian stomodaeum.

Pituitary homeobox (pitx) genes have been identified in vertebrates as critical molecular determinants of various craniofacial ontogenetic processes including pituitary organogenesis. Accordingly, a prominent conserved feature of pitx genes in chordates is their early expression in the anterior neural boundary (ANB) and oral ectoderm, also known as the stomodaeum. Here we used the ascidian model species Ciona intestinalis to investigate pitx gene organization and cis-regulatory logic during early stages of oral development. Two distinct Ci-pitx mRNA variants were found to be expressed in mutually exclusive embryonic domains. Ci-pitx and vertebrate pitx2 genes display remarkably similar exon usage and organization, suggesting ancestry of the pitx transcriptional unit and regulation in chordates. We next combined phylogenetic footprinting, transient transgenesis, and confocal imaging methods to study the Ci-pitx cis-regulatory system, with special emphasis on the regulation of isoform-specific ANB/stomodaeal expression. Among 10 conserved noncoding sequences (CNSs) interspersed in C. intestinalis and Ciona savignyi pitx loci, we identified two separate cis-regulatory modules (CRMs) that drive ANB/stomodaeal expression in complementary spatiotemporal patterns. We discuss the developmental relevance of these data that provide an entry point to investigate the gene regulatory networks (GRNs) that position and shape oral structures in chordates.

Animals↗
PubMed1999

A modular treatment of molecular traffic through the active site of cholinesterase.

We present a model for the molecular traffic of ligands, substrates, and products through the active site of cholinesterases (ChEs). First, we describe a common treatment of the diffusion to a buried active site of cationic and neutral species. We then explain the specificity of ChEs for cationic ligands and substrates by introducing two additional components to this common treatment. The first module is a surface trap for cationic species at the entrance to the active-site gorge that operates through local, short-range electrostatic interactions and is independent of ionic strength. The second module is an ionic-strength-dependent steering mechanism generated by long-range electrostatic interactions arising from the overall distribution of charges in ChEs. Our calculations show that diffusion of charged ligands relative to neutral isosteric analogs is enhanced approximately 10-fold by the surface trap, while electrostatic steering contributes only a 1.5- to 2-fold rate enhancement at physiological salt concentration. We model clearance of cationic products from the active-site gorge as analogous to the escape of a particle from a one-dimensional well in the presence of a linear electrostatic potential. We evaluate the potential inside the gorge and provide evidence that while contributing to the steering of cationic species toward the active site, it does not appreciably retard their clearance. This optimal fine-tuning of global and local electrostatic interactions endows ChEs with maximum catalytic efficiency and specificity for a positively charged substrate, while at the same time not hindering clearance of the positively charged products.

Animals↗
PubMed1987

Electrophysiological evidence for the modular organization of the reticular formation: sympathetic controlling circuits.

Cross-correlation analysis revealed that the discharges of cat medullary reticular neurons located in the recording field of a single microelectrode were synchronized on a time scale of a few ms. The incidence of short time scale interactions was significantly greater when both members of a neuronal pair had activity temporally related to postganglionic inferior cardiac sympathetic nerve discharge than when only one member had sympathetic nerve-related activity. The data support the view that the reticular formation is organized into functionally distinct modules that are potentially interactive.

Animals↗
PubMed2002

Modularity and spatial reorientation in a simple mind: encoding of geometric and nongeometric properties of a spatial environment by fish.

When disoriented in environments with distinctive geometry, such as a closed rectangular arena, human infants and adult rats reorient in accord with the large-scale shape of the environment, but not in accord with nongeometric properties such as the colour of a wall. Human adults, however, conjoined geometric and nongeometric information to reorient themselves, which has led to the suggestion that spatial processing tends to become more flexible over development and evolution. We here show that fish tested in the same tasks perform like human adults and surpass rats and human infants. These findings suggest that the ability to make use of geometry for spatial reorientation is an ancient evolutionary tract and that flexibility and accessibility to multiple sources of information to reorient in space is more a matter of ecological adaptations than phylogenetic distance from humans.

Animals↗
PubMed1999

Control functions of the frontal lobes. Modularity of the central-supervisory system?

Lesions of the prefrontal cortex result in a wide variety of neuropsychological disorders. Despite recent advances, the executive processes and their functional architecture remain poorly specified. This study assessed control processes operating in novel, conflicting and combined tasks in patients with lesion of the prefrontal or posterior cortices. Experiments used two-choice reaction time tests with similar perceptuo-motor and decision processes. It mainly showed (1) impaired short term memory in posterior patients, and (2) impairment of response inhibition and tasks combination in some frontal patients. Selective deficits with double dissociations were evidenced on novel, conflicting and combined tasks. This study provides additional evidence for the prominent role of the frontal lobes in control processes. The demonstration of selective deficits of specific control processes suggests that executive functions depend on multiple separable control processes, and that their operations can be specified in cognitive terms.

Adult↗
PubMed2002

Normalization of nomenclature for peptide motifs as ligands of modular protein domains.

We propose a normalization of symbols and terms used to describe, accurately and succinctly, the detailed interactions between amino acid residues of pairs of interacting proteins at protein:protein (or protein:peptide) interfaces. Our aim is to unify several diverse descriptions currently in use in order to facilitate communication in the rapidly progressing field of signaling by protein domains. In order for the nomenclature to be convenient and widely used, we also suggest a parallel set of symbols restricted to the ASCII format allowing accurate parsing of the nomenclature to a computer-readable form. This proposal will be reviewed in the future and will therefore be open for the inclusion of new rules, modifications and changes.

Binding Sites↗
PubMed2003

The 'antiporter module' of respiratory chain complex I includes the MrpC/NuoK subunit -- a revision of the modular evolution scheme.

Respiratory chain Complex I or NADH:quinone oxidoreductase catalyzes oxidation of NADH in the mitochondrial matrix or bacterial cytoplasm and reduction of quinone in the membrane, coupled to pumping of 4H(+)/2e(-) across the membrane. The same enzyme complex is also capable of the reverse reaction, i.e. Deltamu(H(+))-supported NAD(+) reduction. The molecular mechanism that couples electron transfer to proton pumping is not understood. The Complex I enzyme, containing 14 protein subunits necessary for function, has evolved from smaller functional building blocks. Three Complex I protein subunits, NuoL, NuoM and NuoN, show primary sequence similarity to one particular class of antiporters, and are thus predicted to play a role in the proton translocation machinery. These antiporters, MrpA and MrpD are encoded by a conserved gene cluster, that contains seven genes. In previous work we have determined that these antiporters come in two subclasses, MrpA-type and MrpD-type, and that the Complex I subunit NuoL is more closely related to MrpA and NuoM and N are more closely related to the MrpD antiporter. This implied that both MrpA and MrpD had been recruited to Complex I, rather than arising from gene duplications of one antiporter encoding gene. In this work we show that MrpC and NuoK are homologous proteins. The most plausible explanation for these findings is that a multisubunit antiporter complex was recruited to the ancestral enzyme. We further conclude that the last common ancestor of the Complex I enzyme family and membrane bound NiFe hydrogenases of type 3 and 4 contained the NuoKLMN subunit module.

Amino Acid Sequence↗
PubMed2003

The gelsolin family of actin regulatory proteins: modular structures, versatile functions.

This issue of FEBS Letters includes two manuscripts describing structural studies of gelsolin, the best-characterized member of a superfamily of actin binding proteins that sever, cap, and in some cases nucleate and bundle actin filaments. The manuscripts by Narayan et al. and Irobi et al. provide snapshots of gelsolin domains activated by calcium and in complex with the actin monomer, revealing new insights into the remarkable actin regulatory activities of this versatile protein. These studies build upon nearly a quarter of a century of research on gelsolin's effects on actin dynamics and its role in normal and diseased cells. In the following minireview, we summarize the structural studies that have provided insights into gelsolin's severing and capping activities and look to the future of work on this remarkable molecule.

Actins↗
PubMed1997

The modular phosphorylation and activation of p70s6k.

The activation of p70s6k is accompanied by a complex series of phosphorylation events. In this review we propose a model of activation which divides p70s6k into four functional modules that cooperate in leading to full enzyme activity. In the light of the model, we suggest how candidate effectors of p70s6k activation might function by directing the phosphorylation of specific sites.

Cell Cycle↗
PubMed1998

Kinetic stabilisation of a modular protein by domain interactions.

Protein S, a two-domain spore coat protein from Myxococcus xanthus, is structurally related to eye-lens Pr crystallins. No natural monomeric one-domain member of this protein superfamily is known. To determine the stability of the single domains and to explain the ubiquitous domain duplication, the isolated domains of protein S were constructed. The N-domain is thermodynamically more stable than the C-domain. In intact protein S, domain interactions lead to an apparent decrease in stability of the N-terminal domain, whereas the C-terminal domain is stabilised. In contrast, unfolding kinetics of both domains are decreased 100-fold due to interactions in the complete molecule.

Bacterial Proteins↗
PubMed1999

Structural and functional modularity of voltage-gated potassium channels.

Sequence similarity among known potassium channels indicates the voltage-gated potassium channels consist of two modules: the N-terminal portion of the channel up to and including transmembrane segment S4, called in this paper the 'sensor' module, and the C-terminal portion from transmembrane segment S5 onwards, called the 'pore' module. We investigated the functional role of these modules by constructing chimeric channels which combine the 'sensor' from one native voltage-gated channel, mKv1.1, with the 'pore' from another, Shaker H4, and vice versa. Functional studies of the wild type and chimeric channels show that these modules can operate outside their native context. Each channel has a unique conductance-voltage relation. Channels incorporating the mKv1.1 sensor module have similar rates of activation while channels having the Shaker pore module show similar rates of deactivation. This observation suggests the mKv1.1 sensor module limits activation and the Shaker pore module determines deactivation. We propose a model that explains the observed equilibrium and kinetic properties of the chimeric constructs in terms of the characteristics of the native modules and a novel type of intrasubunit cooperativity. The properties ascribed to the modules are the same whether the modules function in their native context or have been assembled into a chimera.

Animals↗
PubMed2003

Design of a modular immunotoxin connected by polyionic adapter peptides.

Immunotoxins are genetically engineered fusion proteins of an antibody Fv fragment and a toxin from bacteria or plants, which function as anti-cancer therapeutics. Here, we describe a new generation of immunotoxins in which both proteins do not form a single fusion protein but are coupled specifically via cysteine-containing polyionic fusion peptides. The engineered Pseudomonas exotoxin PE38 was N-terminally fused to the peptide E(8)C. In combination with the disulfide-stabilized Fv fragment of the tumor-specific antibody B3, which was extended by the peptide R(8)CP, the fusion peptides ensured a specific and covalent coupling of the Fv fragment and the toxin. The resulting immunotoxin was as active and as specific as an immunotoxin consisting of a fusion protein of the same antibody fragment connected to the toxin.

ADP Ribose Transferases↗
PubMed2003

Designing repeat proteins: modular leucine-rich repeat protein libraries based on the mammalian ribonuclease inhibitor family.

We present a novel approach to design repeat proteins of the leucine-rich repeat (LRR) family for the generation of libraries of intracellular binding molecules. From an analysis of naturally occurring LRR proteins, we derived the concept to assemble repeat proteins with randomized surface positions from libraries of consensus repeat modules. As a guiding principle, we used the mammalian ribonuclease inhibitor (RI) family, which comprises cytosolic LRR proteins known for their extraordinary affinities to many RNases. By aligning the amino acid sequences of the internal repeats of human, pig, rat, and mouse RI, we derived a first consensus sequence for the characteristic alternating 28 and 29 amino acid residue A-type and B-type repeats. Structural considerations were used to replace all conserved cysteine residues, to define less conserved positions, and to decide where to introduce randomized amino acid residues. The so devised consensus RI repeat library was generated at the DNA level and assembled by stepwise ligation to give libraries of 2-12 repeats. Terminal capping repeats, known to shield the continuous hydrophobic core of the LRR domain from the surrounding solvent, were adapted from human RI. In this way, designed LRR protein libraries of 4-14 LRRs (equivalent to 130-415 amino acid residues) were obtained. The biophysical analysis of randomly chosen library members showed high levels of soluble expression in the Escherichia coli cytosol, monomeric behavior as characterized by gel-filtration, and alpha-helical CD spectra, confirming the success of our design approach.

Amino Acid Sequence↗
PubMed1990

Crystallization of Escherichia coli catabolite gene activator protein with its DNA binding site. The use of modular DNA.

To obtain crystals of the Escherichia coli catabolite gene activator protein (CAP) complexed with its DNA-binding site, we have searched for crystallization conditions with 26 different DNA segments greater than or equal to 28 base-pairs in length that explore a variety of nucleotide sequences, lengths, and extended 5' or 3' termini. In addition to utilizing uninterrupted asymmetric lac site sequences, we devised a novel approach of synthesizing half-sites that allowed us to efficiently generate symmetric DNA segments with a wide variety of extended termini and lengths in the large size range (greater than or equal to 28 bp) required by this protein. We report three crystal forms that are suitable for X-ray analysis, one of which (crystal form III) gives measurable diffraction amplitudes to 3 A resolution. Additives such as calcium, n-octyl-beta-D-glucopyranoside and spermine produce modest improvements in the quality of diffraction from crystal form III. Adequate stabilization of crystal form III is unexpectedly complex, requiring a greater than tenfold reduction in the salt concentration followed by addition of 2-methyl-2,4-pentanediol and then an increase in the concentration of polyethylene glycol.

Base Sequence↗
PubMed1983

DNA sequences, gene regulation and modular protein evolution in the Drosophila 68C glue gene cluster.

The 68C locus of the Drosophila melanogaster polytene chromosomes contains the structural genes for three glue polypeptides (sgs-3, sgs-7 and sgs-8) synthesized in the larval salivary glands during the third larval instar. When the messenger RNAs for the glue polypeptides are being synthesized, the locus is puffed; the puff regresses in response to the steroid hormone ecdysterone. The three 68C glue mRNAs are coded in a gene cluster of less than 5000 base-pairs, and are expressed co-ordinately. In the experiments described here we show that the coordinate expression of these RNAs does not result from amplification of the puff DNA, nor is it associated with puff DNA rearrangement. We also report the nucleotide sequence of 6751 base-pairs of genomic DNA that includes the entire gene cluster, and describe coding and non-coding sequences with possible regulatory roles. In addition, we deduce the amino acid sequences of the primary translation products of the glue mRNAs, and show that the glue proteins form a diverged gene family. The members of the family all contain an amino-terminal hydrophobic block of amino acids, which is absent in the mature, secreted glue proteins, and a cysteine-rich carboxy-terminal module. sgs-3 differs from sgs-7 and sgs-8 by containing a third module between the other two, comprised largely of tandem repeats of the five amino acids Pro-Thr-Thr-Thr-Lys.

Amino Acid Sequence↗