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At least 1,279 records · Page 71Linked to original sources
PubMed2005

Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases.

Proteomic experiments have produced a draft profile of the overall molecular composition of the mammalian neuronal synapse. It appears that synapses have over 1000 protein components and the mapping of their interactions, organization and functions will lead to a global view of the role of synapses in physiology and disease. A major functional subcomponent of the synaptic machinery is a multiprotein complex of glutamate receptors and adhesion proteins with associated adaptor and signalling enzymes totally 185 proteins known as the N-methyl-d-aspartate receptor complex/MAGUK associated signalling complex (NRC/MASC). Here, we review the proteomic studies and functions of NRC/MASC and specifically report on the role of its component genes in human diseases. Using a systematic literature search protocol, we identified reports of mutations or polymorphisms in 47 genes associated with 183 disorders, of which 54 were nervous system disorders. A similar number of genes are important in mouse synaptic plasticity and behaviour, where the NRC/MASC acts as a signalling complex with multiple functions provided by its individual protein components and their interactions. The individual gene mutations suggest not only an important role for the NRC/MASC in human diseases but that these diseases may be functionally connected by their common link to the NRC/MASC. The NRC/MASC is a rich source of genetic variation and provides a platform for understanding relationships of disease phenotype amenable to systematic studies such as the Genes to Cognition research consortium (www.genes2cognition.org) that links human and mouse genetics with proteomic studies.

Humans↗
PubMedDate not supplied

Automatic annotation of BIND molecular interactions from three-dimensional structures.

Software to automate the process of extracting molecular interactions from three-dimensional (3D) structures has been developed that records these as Biomolecular Interaction Network Database (BIND) pairwise interaction records. Full annotation of BIND records is provided through a database processing tool called MMDBind, including detailed atom-atom and residue-residue level interaction information. BIND three-dimensional interaction annotation is synthesized by combining information from the Molecular Modeling Database (MMDB), and the HET (heterogen) group dictionary of small molecules in the macromolecular Crystallographic Information Format (mmCIF). Interactions are validated using the Protein Quaternary Structure (PQS) system. A total of 18,166 interactions were removed as being redundant or biologically irrelevant after PQS validation. This first pass MMDBind annotation creates two new divisions of BIND, 3D Biopolymers (BIND-3DBP) comprising 16,737 initial interaction records, and 3D Small Molecules (BIND-3DSM) comprising 48,219 records. Visualization of interacting residues and nucleotides within a macromolecular structure is possible directly from the BIND database owing to added 3D feature annotation within the BIND records that can be conveniently seen using Cn3D ("see-in-3D") after query from the BIND Data Manager. These interaction records provide a further demonstration of the completeness of the BIND data specification and its capabilities as storage and exchange format for all kinds of molecular interactions, including RNA, DNA, protein, and small molecules. Data from the 3DBP and 3DSM sets are available for downloading in Abstract Syntax Notation.1 (ASN.1) or Extensible Markup Language (XML) formats at ftp://ftp.bind.ca/DB/MMDBBind. Data from the 3DBP set is available for interactive query from the BIND Data Manager at www.bind.ca.

Crystallography, X-Ray↗
PubMed1976

Collecting and processing records from the ultracentrifuge in "real-time" using an on-line computer.

An analytical system consisting of an analytical cantrifuge coupled 'on-line' to a computer was assembled and tested. Collection of records from up to 9 solutions was achieved through programmes which sum readings to reduce noise as well as controlling the positioning of the scanner. With this system it was found that the limit on accuracy for molecular weights at concentrations less than 0.01 g cm-3 was +/- 3% estimated from sedimentation equilibrium experiments. The same system was used to collect records for similar concentrations from velocity experiments by employing a scanning schlieren. In this case the accuracy in estimating sedimentation coefficients was similar to those found when measuring photographs. Since the collection yields detailed information about the shape of the sedimenting boundary, the centroids of the boundary were routinely computed by second moment analysis rather than relying on the position of the maximum of the schlieren peak. In the same analysis estimates of diffusion coefficients were made routinely by calculating corrected height/area ratios for each scan. These calculations were made during the real-time of the experiment, so making available molecular parameters rather than records which must be evaluated some time after stopping the experiment.

Computers, Hybrid↗
PubMedDate not supplied

Ethanol modulates coronary permeability to macromolecules in murine AIDS.

BACKGROUND AND AIMS: The cardiovascular complications of AIDS are serious. However, the underlying mechanisms are unclear. Less is known about how ethanol affects the coronary microcirculation in individuals with AIDS. The aim of this study was to assess the integrity of the coronary microcirculation in murine AIDS mice in the presence or absence of chronic ethanol consumption. METHODS: Four groups were studied: control, murine AIDS, ethanol and ethanol plus murine AIDS. Mouse hearts were prepared for direct visualization of the coronary microcirculation and quantification of trans-coronary macromolecular leakage. Hearts were isolated and perfused with diluted rat blood containing fluorescein isothiocyanate-albumin (FITC-BSA). Coronary vessels were observed using intravital fluorescence microscopy after 5, 15 and 25 min of perfusion. The mean luminosity of outside/inside coronary vessels (O/I ratio) was used to quantify FITC-BSA leakage. RESULTS: We found that the mean O/I ratio for the murine AIDS group was significantly greater than in the control group and also significantly increased during the perfusion period. Chronic ethanol consumption did not alter coronary permeability to macromolecules, but improved the coronary haemodynamics in murine AIDS. CONCLUSIONS: These findings suggest that murine AIDS impairs the structural and functional coronary endothelium, and moderate ethanol consumption modulates the function of the coronary microcirculation.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Architecture of the ParF*ParG protein complex involved in prokaryotic DNA segregation.

The mechanism by which low copy number plasmids are segregated at cell division involves the concerted action of two plasmid-encoded proteins that assemble on a centromere-like site. This study explores the topology of the DNA segregation machinery specified by the parFG locus of TP228, a partition system which is phylogenetically distinct from more well-characterized archetypes. A variety of genetic, biochemical and biophysical strategies revealed that the ParG protein is dimeric. ParF, which is more closely related to the cell division regulator MinD than to the prototypical ParA partition protein of plasmid P1, is instead multimeric and its polymeric state appears to be modulated by ATP which correlates with the proposed ATP-binding activity of ParF. ParG interacts in a sequence-specific manner with the DNA region upstream of the parFG locus and this binding is modulated by ParF. Intriguingly, the ParF and ParG proteins form at least two types of discrete complex in the absence of this region suggesting that the assembly dynamics of these proteins onto DNA is intricate.

Adenosine Triphosphate↗
PubMed2003

Long-lasting CNS effects of a short-term chemical knockout of ornithine decarboxylase during development: nicotinic cholinergic receptor upregulation and subtle macromolecular changes in adulthood.

Ornithine decarboxylase (ODC) and the polyamines play an essential role in brain cell replication and differentiation and polyamines also regulate the function of nicotinic acetylcholine receptors (nAChRs). We administered alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, to neonatal rats on postnatal days 5-12, during the mitotic peak of the cerebellum, a treatment regimen that achieves a chemical knockout of ODC activity and polyamine depletion limited to the treatment period. Although growth inhibition and gross dysmorphology were limited to the cerebellum, both alpha7 and alpha4beta2 nAChRs were upregulated in adulthood in the frontal cortex, hippocampus and thalamus, with the largest effect in the latter region, primarily in females. Receptor upregulation was accompanied by abnormalities in macromolecular indices of cell packing density and cell membrane surface area, but the generalized cellular alterations did not share the regional or sex selectivity shown by the effects on nAChRs. Elevated DNA concentration was most notable in the hippocampus and was associated with augmented levels of glial fibrillary acidic protein, thus implying gliosis as the cause of the increased number of cells. DFMO's effects on both nAChR expression and cellular biomarkers resembled those of developmental exposure to nicotine. Accordingly, some of the effects may represent a specific alteration in nAChR signaling evoked by polyamine depletion during a critical developmental window. Alterations in polyamine gating of cholinergic synaptic signaling may thus contribute to the adverse neurobehavioral effects of numerous neuroteratogens that directly or indirectly disrupt the ODC/polyamine pathway.

Animals↗
PubMed1987

Tertiary structure of histidine-containing protein of the phosphoenolpyruvate:sugar phosphotransferase system of Escherichia coli.

The tertiary structure of the histidine-containing phosphocarrier protein (HPr) of the Escherichia coli phosphoenolpyruvate:sugar phosphotransferase system has been determined by x-ray diffraction at 2.8-A resolution. Initially, a partial structure was fitted to the multiple isomorphous replacement map and then least-squares refined by the Konnert/Hendrickson restrained parameter method (Konnert, J. H., and Hendrickson, W. A. (1980) Acta Crystallogr. A36, 344-350) and finally, a subsequent map was computed by use of the phase combination method of Read (Read, R. J. (1986) Acta Crystallogr. A42, 140-149). More of the protein structure was located in the latter map. The procedure of model building, least-squares refinement, and electron density map recalculation was repeated until the tertiary structure of HPr was obtained. The overall structure of HPr consists of four beta-strands, three helical regions, and four beta-turns. At the active center, the His15 imidazole interacts with one oxygen atom of the alpha-carboxyl C terminus of the polypeptide chain; the conserved Arg17 side chain interacts with the other oxygen atom of the alpha-carboxyl C terminus as well as with the side chain of Glu85. This is the first x-ray analysis of a protein of the phosphoenolpyruvate:sugar phosphotransferase system. Furthermore, this work represents a protein structure which has been solved by starting with a model that represented only one-third of the scattering matter.

Escherichia coli↗
PubMed1986

Clotrimazole, an inhibitor of benzo[a]pyrene metabolism and its subsequent glucuronidation, sulfation, and macromolecular binding in BALB/c mouse cultured keratinocytes.

The effect of the antifungal imidazole compound, clotrimazole, on the metabolism of benzo[a]pyrene (BP) was studied in cultured keratinocytes prepared from BALB/c mouse epidermis. Varying concentrations of clotrimazole added to the cultured keratinocytes resulted in a dose-dependent inhibition of the activities of the microsomal cytochrome P-450-dependent monooxygenases aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The major organic solvent-soluble metabolites of BP identified in the cultured cells were trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (BP-7,8-diol), 9-hydroxybenzo[a]pyrene (9-OH-BP), and 3-hydroxybenzo[a]pyrene (3-OH-BP), although small amounts of trans-4,5-dihydro-4,5-dihydroxybenzo[a]pyrene, BP-quinones, and trans-9,10-dihydroxybenzo[a]pyrene were also present. The major organic solvent-extractable metabolites of BP found in the extracellular culture medium were primarily the diols with smaller quantities of phenols and quinones. The major water-soluble metabolites of BP present both intracellularly and extracellularly were glucuronide conjugates of 3-OH-BP, 9-OH-BP, and benzo[a]pyrene-3,6-dione and to a lesser extent sulfate conjugates (primarily of the BP-7,8-diol). Clotrimazole inhibited the generation of organic solvent-soluble and water-soluble conjugates in a dose-dependent manner. The in vitro metabolism of BP by microsomes prepared from control and benz[a]anthracene (BA)-induced cultured keratinocytes was also inhibited by clotrimazole with greater inhibitory effect on BA-induced keratinocytes especially with respect to the formation of diols and quinones. The enzyme-mediated covalent binding of BP to mouse keratinocyte DNA and protein was also substantially diminished by clotrimazole in a dose-dependent fashion. These results indicate that clotrimazole, a widely used drug for the management of a variety of superficial dermatophyte infections of the skin, is a potent inhibitor of cytochrome P-450-dependent transformation of polycyclic aromatic hydrocarbons in cultured murine keratinocytes. This system offers a convenient approach for studies as inhibitors of carcinogen metabolism in the epidermis.

Animals↗
PubMed1995

Drug delivery studies in Caco-2 monolayers. IV. Absorption enhancer effects of cyclodextrins.

PURPOSE: The purpose of the present study was to use the human colorectal carcinoma cell line. Caco-2, as a human intestinal epithelial model for studying the effects of cyclodextrins as absorption enhancers. METHODS: Cyclodextrins of varying sizes and physicochemical characters were investigated. The effects of the cyclodextrins were evaluated by means of staining of the cytoplasma and determination of the mitochondrial dehydrogenase activity as well as by transport enhancement of the macromolecular pore marker polyethylene glycol 4000 (PEG-4000) across the Caco-2 monolayers. RESULTS: The transport enhancing properties of the cyclodextrins were found to follow the lipophilicity of the core in their cyclic structure. Dimethyl-beta-cyclodextrin was the most powerful in all aspects and caused an increase in the permeability of the cytoplasma membrane in a concentration dependent manner. It was possible to increase the overall transport of PEG-4000 10-fold by the use of dimethyl-beta-cyclodextrin in low concentrations where the toxic effects on the monolayers were insignificant. It was further observed that the basolateral membrane was significantly more sensitive to cyclodextrins than the apical membrane. CONCLUSIONS: Since dimethyl-beta-cyclodextrin was able to produce an absorption enhancing effect on PEG-4000 in concentrations where the toxic effects on Caco-2 monolayers were low it is worth to pursue the compound as an absorption enhancer.

Biological Transport, Active↗
PubMed2005

Microchannel systems in titanium and silicon for structural and mechanical studies of aligned protein self-assemblies.

We report a technique for the alignment of self-assembled protein systems, such as F-actin bundles and microtubules, in a surface-modified titanium or silicon microfluidic device. Assembling filamentous protein systems in a confined geometry produces highly aligned samples for structural and mechanical studies. Biomolecular self-assembly can be investigated in a controlled fashion under different molecular concentration gradients and conditions along a channel length. We have shown that surface-modified devices produced via a high aspect ratio etch process in titanium and silicon can be used to confine and control such macromolecular assemblies and present examples of F-actin bundles and microtubules in this system.

Actins↗
PubMed2001

Network dynamics and cell physiology.

Complex assemblies of interacting proteins carry out most of the interesting jobs in a cell, such as metabolism, DNA synthesis, movement and information processing. These physiological properties play out as a subtle molecular dance, choreographed by underlying regulatory networks. To understand this dance, a new breed of theoretical molecular biologists reproduces these networks in computers and in the mathematical language of dynamical systems.

CDC2 Protein Kinase↗
PubMed1996

Deuterium off-resonance rotating frame spin-lattice relaxation of macromolecular bound ligands.

Deuterated 3-trimethylsilylpropionic acid binding to bovine serum albumin was used as a model system to examine the feasibility and limitations of using the deuterium off-resonance rotating frame spin-lattice relaxation experiment for the study of equilibrium ligand-binding behavior to proteins. The results of this study demonstrate that the rotational-diffusion behavior of the bound species can be monitored directly, i.e., the observed correlation time of the ligand in the presence of a protein is approximately equal to the correlation time of the ligand in the bound state, provided that the fraction of bound ligand is at least 0.20. The presence of local ligand motion and/or chemical exchange contributions to relaxation in the bound state was inferred from the observation that the correlation time of the bound ligand was somewhat smaller than the correlation time characterizing the overall tumbling of the protein. An approximate value for the fraction of bound ligand was obtained from off-resonance relaxation experiments when supplemental spin-lattice or transverse relaxation times were employed in the analysis. Incorporation of local motion effects for the bound species into the theoretical relaxation formalism enabled the evaluation of an order parameter and an effective correlation time, which in conjunction with a wobbling in a cone model, provided additional information about ligand motion in the bound state.

Animals↗
PubMed1999

Pharmacokinetics of anticancer drugs, plasmid DNA, and their delivery systems in tissue-isolated perfused tumors.

To achieve an optimal chemotherapy or gene therapy against tumors or to realize rational design of delivery systems for cancer therapy, pharmacokinetic information in tumor should be obtained. A tissue-isolated tumor preparation is a useful experimental system to investigate the intratumoral disposition of drugs, carriers, and their complexes. The disposition of drugs in the solid tumor was analyzed in this system after intraarterial infusion (systemic route) or by intratumoral injection (topical route). Here the results of low-molecular weight drugs, their macromolecular prodrugs, lipid carriers like fat emulsions and liposomes, and plasmid DNA and its complexes, are addressed. Pharmacokinetic analyses in the tumor clearly indicate that the intratumoral fate of drugs and delivery systems are determined by (i) the anatomical and physiological properties of the tissue and (ii) the physicochemical characteristics of drugs and delivery systems such as molecular weight, size, lipophilicity, and electrical charge. These approaches are useful for designing and developing optimized drug delivery systems.

Journal Article↗
PubMed2003

Design strategies to improve soluble macromolecular delivery constructs.

Macromolecular therapeutics provide numerous benefits for the delivery of cytotoxic or poorly soluble drugs in vivo. However, these constructs often encounter barriers for drug delivery on both the systemic and subcellular level. Many soluble polymer carriers have been designed to surmount specific physiological barriers individually, but less work has been dedicated to designing an all-encompassing construct that addresses multiple therapeutic barriers at once. Incorporation of multiple agents already individually known to increase effectiveness into one carrier could further improve current drug delivery technology. Recent developments in subcellular delivery of therapeutic agents in soluble macromolecular carriers are discussed in the context of the future possibility for the design of an all-encompassing soluble multi-functional drug delivery vehicle.

Animals↗
PubMed1980

Compartmentalization of self-reproducing machineries: multiplication of microsystems with self-instructing polymerization of amino acids.

A theoretical model is presented for the self-instructing polymerization of free amino acids which proceeds inside microsystems which are phase-separated from the solution of thermal polyamino acids. It is shown theoretically that a compartmentalized microsystem fixes inside itself only the process with a faster macromolecular multiplication as time passes, even if the catalytic polymerization alone could spontaneously decrease the corresponding reaction rate. The compartmentalized machinery of macromolecular multiplication cannot reach its stationary state. The machinery is inevitably multiplied and alternates with those with either faster rates of macromolecular multiplication or slower rates of macromolecular degradation during their time development. These results are based upon the dynamic process that any material system acts by itself so as to remove any flow disequilibrium, that is, to maintain the continuity of material flow.

Amino Acids↗
PubMed1992

Mechanics of solute translocation catalyzed by enzyme IImtl of the phosphoenolpyruvate-dependent phosphotransferase system of Escherichia coli.

The kinetics of binding of mannitol to enzyme IImtl embedded in the membrane of vesicles with an inside-out or a right-side-out orientation were analyzed at 4 degrees C in the absence of the phosphoryl group donor, P-HPr. The binding to the right-side-out oriented vesicles equilibrated too fast to be monitored by the flow dialysis technique. On the other hand, with the inside-out oriented membrane vesicles two conformational changes of the enzyme could be detected kinetically. One change involved a recruitment of binding sites from a state of the enzyme where the binding sites were inaccessible from the cytoplasmic volume. The second change involved a conformational change of the enzyme that followed upon the initial binding to the cytoplasmic-facing binding site leading to a state with a higher affinity for mannitol. Equilibrium binding to the inside-out and right-side-out oriented membrane vesicles at 4 degrees C indicated that the two transitions did not represent the translocation of the binding site, free and with mannitol bound to it, to the other side of the membrane. Instead, a model is proposed in which the conformational changes represent transitions from states with the binding pocket opened to the cytoplasmic side of the membrane to occluded states of the enzyme in which the binding sites, with or without mannitol bound, are not accessible to either side of the membrane.

Binding Sites↗