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PubMed2001

Structure of an active soluble mutant of the membrane-associated (S)-mandelate dehydrogenase.

The structure of an active mutant of (S)-mandelate dehydrogenase (MDH-GOX2) from Pseudomonas putida has been determined at 2.15 A resolution. The membrane-associated flavoenzyme (S)-mandelate dehydrogenase (MDH) catalyzes the oxidation of (S)-mandelate to give a flavin hydroquinone intermediate which is subsequently reoxidized by an organic oxidant residing in the membrane. The enzyme was rendered soluble by replacing its 39-residue membrane-binding peptide segment with a corresponding 20-residue segment from its soluble homologue, glycolate oxidase (GOX). Because of their amphipathic nature and peculiar solubilization properties, membrane proteins are notoriously difficult to crystallize, yet represent a large fraction of the proteins encoded by genomes currently being deciphered. Here we present the first report of such a structure in which an internal membrane-binding segment has been replaced, leading to successful crystallization of the fully active enzyme in the absence of detergents. This approach may have general application to other membrane-bound proteins. The overall fold of the molecule is that of a TIM barrel, and it forms a tight tetramer within the crystal lattice that has circular 4-fold symmetry. The structure of MDH-GOX2 reveals how this molecule can interact with a membrane, although it is limited by the absence of a membrane-binding segment. MDH-GOX2 and GOX adopt similar conformations, yet they retain features characteristic of membrane and globular proteins, respectively. MDH-GOX2 has a distinctly electropositive surface capable of interacting with the membrane, while the opposite surface is largely electronegative. GOX shows no such pattern. MDH appears to form a new class of monotopic integral membrane protein that interacts with the membrane through coplanar electrostatic binding surfaces and hydrophobic interactions, thus combining features of both the prostaglandin synthase/squaline-hopine cyclase and the C-2 coagulation factor domain classes of membrane proteins.

Alcohol Oxidoreductases↗

PubMedDate not supplied

[Cellular mechanisms of conditioned reflex integration].

The paper deals with the formation of cellular mechanisms of integration in the course of conditioned reflex elaboration. Primary integration consists in an interaction between the effects of the conditioned (CS) and unconditioned (US) stimuli on neurons, which leads to a stable connection between them. The subsequent, final integration consists in the joining up of these cells into special populations with common functional properties in relation to the paired stimuli. Primary integration is achieved either by the mechanism of addition of the elaborated reaction to the CS to the response to the US, or by joining an adequate reaction to the CS of the elaborated response to the US. The final integration is apparently achieved by the mechanisms of transmition from one neuron to another of the formed connection between the paired stimuli along one path common for the association as a whole.

Animals↗

PubMed2003

Integrating measurement of control and affiliation in studies of physician-patient interaction: the interpersonal circumplex.

Following a brief overview and commentary on the physician-patient communication literature, this article summarizes and evaluates research on the relationship between physician-patient control (dominant-submissive) and affiliation (friendly hostile) behaviors as they relate to medical outcomes. Findings for both verbal and nonverbal control and affiliation measures are included. The interpersonal circumplex (together with the important interactional principles that it incorporates) is then introduced as an heuristic guide for future medical interaction research. The circumplex was constructed as a conceptual and empirical model to integrate the numerous studies that have established control and affiliation as universal dimensions of human interpersonal behavior and relationships. Next, the small group of studies that have applied circumplex inventories to analyses of practitioner-patient transactions are reviewed with emphasis on their strengths and unique aspects of their findings. The concluding section enumerates advantages and innovations that the interpersonal circumplex and its measures can provide to facilitate more heuristic studies of physician-patient interactions.

Communication↗

PubMed2001

Hox genes, neural crest cells and branchial arch patterning.

Proper craniofacial development requires the orchestrated integration of multiple specialized tissue interactions. Recent analyses suggest that craniofacial development is not dependent upon neural crest pre-programming as previously thought but is regulated by a more complex integration of cell and tissue interactions. In the absence of neural crest cells it is still possible to obtain normal arch patterning indicating that neural crest is not responsible for patterning all of arch development. The mesoderm, endoderm and surface ectoderm tissues play a role in the patterning of the branchial arches, and there is now strong evidence that Hoxa2 acts as a selector gene for the pathways that govern second arch structures.

Animals↗

PubMed2005

PHR1, an integral membrane protein of the inner ear sensory cells, directly interacts with myosin 1c and myosin VIIa.

By using the yeast two-hybrid technique, we identified a candidate protein ligand of the myosin 1c tail, PHR1, and found that this protein can also bind to the myosin VIIa tail. PHR1 is an integral membrane protein that contains a pleckstrin homology (PH) domain. Myosin 1c and myosin VIIa are two unconventional myosins present in the inner ear sensory cells. We showed that PHR1 immunoprecipitates with either myosin tail by using protein extracts from cotransfected HEK293 cells. In vitro binding assays confirmed that PHR1 directly interacts with these two myosins. In both cases the binding involves the PH domain. In vitro interactions between PHR1 and the myosin tails were not affected by the presence or absence of Ca2+ and calmodulin. Finally, we found that PHR1 is able to dimerise. As PHR1 is expressed in the vestibular and cochlear sensory cells, its direct interactions with the myosin 1c and VIIa tails are likely to play a role in anchoring the actin cytoskeleton to the plasma membrane of these cells. Moreover, as both myosins have been implicated in the mechanotransduction slow adaptation process that takes place in the hair bundles, we propose that PHR1 is also involved in this process.

Animals↗

PubMed2003

Nucleocytoplasmic transport: taking an inventory.

In eukaryotic cells, the enclosure of the genetic information in the nucleus allows the spatial and temporal separation of DNA replication and transcription from cytoplasmic protein synthesis. This compartmentalization not only permits a high level of regulation of these processes but at the same time necessitates a system of selective macromolecular transport between the nucleus and the cytoplasm. Transfer of macromolecules between both compartments is mediated by soluble receptors that interact with components of nuclear pore complexes (NPCs) to move their specific cargos. Transport occurs by way of a great variety of different pathways defined by individual receptors and accessory factors. Often, processes in substrate biogenesis that precede transport concurrently recruit transport factors to substrates, thus making transport responsive to correct and orderly synthesis of substrates. Some current challenges are to understand how transport factor-substrate interactions are controlled and integrated with sequential steps in substrate biogenesis, how large macromolecular complexes are restructured to fit through the NPC channel and to understand how transport factor-NPC interactions lead to actual translocation through the NPC.

Active Transport, Cell Nucleus↗

PubMed2005

A three-dimensional model of the human immunodeficiency virus type 1 integration complex.

While the general features of HIV-1 integrase function are understood, there is still uncertainty about the composition of the integration complex and how integrase interacts with viral and host DNA. We propose an improved model of the integration complex based on current experimental evidence including a comparison with the homologous Tn5 transposase containing bound DNA and an analysis of DNA binding sites using Goodford's GRID. Our model comprises a pair of integrase dimers, two strands of DNA to represent the viral DNA ends and a strand of bent DNA representing the host chromosome. In our model, the terminal four base pairs of each of the viral DNA strands interact with the integrase dimer providing the active site, while bases one turn away interact with a flexible loop (residues 186-194) on the second integrase dimer. We propose that residues E152, Q148 and K156 are involved in the specific recognition of the conserved CA dinucleotide and that the active site mobile loop (residues 140-149) stabilises the integration complex by acting as a barrier to separate the two viral DNA ends. In addition, the residues responsible for DNA binding in our model show a high level of amino acid conservation.

Amino Acid Sequence↗

PubMed2006

Interactive continuously moving table (iCMT) large field-of-view real-time MRI.

Continuously moving table (CMT) MRI is a new method that is capable of generating 3D, seamless, large field-of-view (FOV) images by acquiring readouts along the patient superior-inferior axis as the subject is translated through the scanner. For applications that require artifact-free images, such as arterial-phase contrast-enhanced (CE) angiography of the legs, a major challenge is to match the MR data acquisition and patient table motion with the dynamics of blood flow in the region of interest (ROI). Instead of restricting the CMT to predetermined constant table speeds, we adopted a more general approach in which the table motion is decoupled from the phase-encoding order. In our approach the table moves adaptively and in response to operator-provided feedback obtained from viewing real-time preview (or fluoroscopic) images. This interactivity is accomplished by integrating high temporal-spatial resolution encoding of the table position with real-time hybrid-space filling and image reconstruction. Experimental results obtained using our prototype interactive CMT (iCMT) system on a peripheral vascular phantom and five healthy volunteers demonstrate the feasibility of this robust and rapid imaging method for acquiring 3D large-FOV continuous images with patient-specific adaptive table motion profiles.

Beds↗

PubMed2000

Functional properties of sodium channels do not depend on the cytoskeleton integrity.

Several observations suggest an interaction of the sodium channel alpha-subunit with the cytoskeletal structures. However, there is a wide variability in the results of experiments of heterologous expression in Xenopus oocytes and studies on mammalian cells are sometimes contradictory. In general, there has been no direct demonstration that ad hoc large perturbations of the cytoskeleton modify the intrinsic properties of the sodium channels expressed endogenously or heterologously in plasma membranes. We have studied in CHO cells transfected with the rat muscle sodium channel alpha-subunit the effects of two substances expected to produce drastic perturbations of the cytoskeletal structure: Cytochalasin-D, which depolymerizes microfilaments, and Colchicine, which inhibits the microtubules polymerization. We observed no significant differences in the voltage dependence, kinetic parameters and surface density of the expressed sodium channels after treatment of the cells with these substances. We conclude that the two known main components of the cytoskeleton do not interfere directly with the sodium channel function or with the heterologous expression of channels in the cell membrane.

Actin Cytoskeleton↗

PubMed2000

Functional properties of sodium channels do not depend on the cytoskeleton integrity.

Animals↗

PubMedDate not supplied

In vitro and in vivo effect of immunoglobulin G on the integrity of bacterial membranes.

The interaction between a modified 7S immunoglobulin (MISG) and bacterial membranes was studied by adopting in vitro as well as in vivo techniques. Preincubation of Escherichia coli and Pseudomonas aeruginosa with MISG resulted in a release of enzymatic markers from the periplasmic space, whereas no cytoplasmic or membrane-bound enzymes were liberated. Due to the interaction of MISG with the outer membrane of gram-negative rods, the bacteria became more susceptible to the antibacterial action of poorly penetrating penicillins because of a significantly increased rate of uptake. These in vitro effects were corroborated under in vivo conditions by adopting the granuloma pouch model. A single intravenous injection of MISG enhanced the therapeutic efficacy of mezlocillin against E. coli; similarly, the antibacterial activity of penicillin G, oxacillin, cephalothin and cefamandole against Staphylococcus aureus was augmented by MISG. These in vivo effects of MISG were not due to an increased rate of phagocytosis or complement activity. Thus, MISG sensitized bacteria to several beta-lactam antibiotics by disorganizing their outer membrane.

Animals↗

PubMed1985

In vitro and in vivo effect of immunoglobulin G on the integrity of bacterial membranes.

Anti-Bacterial Agents↗

PubMed2003

Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization.

Several protein complexes that are involved in epithelial apicobasal polarity have been identified. However, the mechanism by which these complexes interact to form an integrated polarized cell morphology remains unclear. Crumbs (Crb) and Lethal giant larvae (Lgl) are components of distinct complexes that regulate epithelial polarization in Drosophila melanogaster, but may not interact directly as they localize to the apical and basolateral membrane, respectively. Nevertheless, a genetic screen identifies marked functional interactions between crb and lgl. These interactions extend to other genes within the crb (stardust, sdt) and lgl (discs large, dlg; scribble, scrib) pathways. Our findings suggest that the crb and lgl pathways function competitively to define apical and basolateral surfaces. They also suggest that in the absence of lgl pathway activity, the crb pathway is not required to maintain epithelial polarity. Moreover, we show that crb and lgl cooperate in zonula adherens formation early in development. At later stages, epithelial cells in these mutants acquire normal polarity, indicating the presence of compensatory mechanisms. We find that bazooka (baz) functions redundantly with crb/sdt to support apical polarity at mid- to late-embryogenesis. Despite regaining cell polarity, however, epithelial cells in crb and lgl pathway mutants fail to re-establish normal overall tissue architecture, indicating that the timely acquisition of polarized cell structure is essential for normal tissue organization.

Animals↗

PubMed1998

The major nuclear envelope targeting domain of LAP2 coincides with its lamin binding region but is distinct from its chromatin interaction domain.

LAP2 is an integral protein of the inner nuclear membrane which binds lamins and chromosomes and is suggested to have an important role in nuclear envelope organization. In a previous study we identified an internal 76-amino acid region of LAP2 which is required for stable targeting of the protein to the nuclear envelope. Here, we have mapped the lamin binding region of LAP2 and demonstrate that it coincides with this nuclear envelope targeting domain. In contrast, we found that the portion of LAP2 involved in binding to chromosomes resides in a separate region of the protein near its NH2 terminus. The minimal lamin binding region of LAP2 is capable of conferring stable nuclear envelope localization when attached to the transmembrane and partial lumenal domains of a protein that shows no nuclear envelope targeting activity. This directly supports the notion that a major mechanism for localization of integral membrane proteins at the inner nuclear membrane involves binding to lamins, which would constrain diffusion through the continuous nuclear envelope/endoplasmic reticulum membrane system.

Binding Sites↗

PubMed1996

Co-culture of contiguous developmental fields in a serumless, chemically-defined medium: an in vitro model permissive for coordinate development of the mouse ear.

Pattern formation is intrinsically hierarchical, increasing in complexity from the first early embryonic inductive tissue interactions to the eventual integration of multiple organ systems. Viewed as a problem in pattern formation, the vertebrate ear is an exceedingly complex organ system in which normal morphogenesis requires multiple inductive interactions between a variety of adjacent tissues. In order to model the process of higher level pattern formation, we have developed a method for organ culture of the embryonic murine ear. E10.5 mouse embryos (38 to 42 somite pairs) were microdissected into explants that consist of the first and second branchial arches, the otocyst, and the adjacent neural tube. The growth of these explants in a serumless, chemically-defined medium was compared to medium supplemented with 10% fetal calf serum. After 6 days in culture using serumless medium, we observed that this environment was permissive for the formation of pinnae, rudimentary semicircular canals and cochlear ducts, chondrogenesis of the otic capsule and elongation of the endolymphatic ducts. Posterior elements of Meckel's and Reichert's cartilages were identified as ossicular anlagen. All of these structures maintained appropriate anatomic interrelationships during in vitro development. Furthermore, no significant differences were observed in explants grown in serum-supplemented medium. We conclude that during ear development several histogenetic and morphogenetic processes, including aspects of higher level pattern formation, are mediated primarily by paracrine and/or autocrine factors. The development of an organ culture model using serumless medium should facilitate the discovery of intrinsic factors which regulate the coordinate development of inner, middle and external ear structures.

Animals↗

PubMed2006

Drug permeability across a phospholipid vesicle based barrier: 3. Characterization of drug-membrane interactions and the effect of agitation on the barrier integrity and on the permeability.

Recently, we reported on the development and structural characterization of a phospholipid vesicle based barrier useful for medium throughput screening of passive drug permeability. Here, we investigate the physical and functional integrity of the phospholipid vesicle based barriers to agitation by stirring or shaking, and whether agitation affects drug permeability of sulpiride, metoprolol and testosterone. In addition, three drugs (caffeine, naproxen and sulphasalazine) which were shown in a previous study to affect the electrical resistance of the barriers, were investigated for their influence on the permeability of a simultaneously applied hydrophilic marker (calcein), and on the thermotropic phase transition of the phospholipid bilayers using differential scanning calorimetry (DSC). Electrical resistance measurements indicated that the barriers should withstand shaking speeds up to 150rpm without losing their integrity, but significant release of phospholipids from the membrane barriers to the donor and acceptor chambers was observed under agitation >or=150rpm. When using agitation up to 100rpm no increase in permeability was observed for sulpiride, metoprolol and testosterone. The phospholipid vesicle-based barrier thus differ from other permeability models in that agitation does not lead to an increase in permeability, not even for highly lipophilic drugs such as testosterone. This is explained by the different morphology of the vesicle-based barrier which is containing a 100microm thick layer of mostly aqueous compartments immobilised within a matrix of phospholipids vesicles. Sulphasalazine and naproxen were shown to decrease the electrical resistance and increase the permeability of the hydrophilic marker calcein. The DSC experiments showed that these two drugs probably interact with the head groups of the phospholipids. In contrast, caffeine gave an increase in electrical resistance and a decrease in permeability of calcein. From the DSC experiments no signs of interaction of caffeine with the phospholipid bilayer could be observed.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Effect of temperature on maximum swimming speed and cost of transport in juvenile European sea bass (Dicentrarchus labrax).

This study is an attempt to gain an integrated understanding of the interactions between temperature, locomotion activity and metabolism in the European sea bass (Dicentrarchus labrax). To our knowledge this study is among the few that have investigated the influence of the seasonal changes in water temperature on swimming performance in fish. Using a Brett-type swim-tunnel respirometer the relationship between oxygen consumption and swimming speed was determined in fish acclimatised to 7, 11, 14, 18, 22, 26 and 30 degrees C. The corresponding maximum swimming speed (U(max)), optimal swimming speed (U(opt)), active (AMR) and standard (SMR) metabolic rates as well as aerobic metabolic scope (MS) were calculated. Using simple mathematical functions, these parameters were modelled as a function of water temperature and swimming speed. Both SMR and AMR were positively related to water temperature up to 24 degrees C. Above 24 degrees C SMR and AMR levelled off and MS tended to decrease. We found a tight relationship between AMR and U(max) and observed that raising the temperature increased AMR and increased swimming ability. However, although fish swam faster at high temperature, the net cost of transport (COT(net)) at a given speed was not influence by the elevation of the water temperature. Although U(opt) doubled between 7 degrees C and 30 degrees C (from 0.3 to 0.6 m s(-1)), metabolic rate at U(opt) represented a relatively constant fraction of the animal active metabolic rate (40-45%). A proposed model integrates the effects of water temperature on the interaction between metabolism and swimming performance. In particular the controlling effect of temperature on AMR is shown to be the key factor limiting maximal swimming speed of sea bass.

Analysis of Variance↗

PubMed2002

Interactions among the protein and RNA subunits of Saccharomyces cerevisiae nuclear RNase P.

Ribonuclease P (RNase P) is a ubiquitous endoribonuclease that cleaves precursor tRNAs to generate mature 5' termini. Although RNase P from all kingdoms of life have been found to have essential RNA subunits, the number and size of the protein subunits ranges from one small protein in bacteria to at least nine proteins of up to 100 kDa. In Saccharomyces cerevisiae nuclear RNase P, the enzyme is composed of ten subunits: a single RNA and nine essential proteins. The spatial organization of these components within the enzyme is not yet understood. In this study we examine the likely binary protein-protein and protein-RNA subunit interactions by using directed two- and three-hybrid tests in yeast. Only two protein subunits, Pop1p and Pop4p, specifically bind the RNA subunit. Pop4p also interacted with seven of the other eight protein subunits. The remaining protein subunits all showed one or more specific protein-protein interactions with the other integral protein subunits. Of particular interest was the behavior of Rpr2p, the only protein subunit found in RNase P but not in the closely related enzyme, RNase MRP. Rpr2p interacts strongly with itself as well as with Pop4p. Similar interactions with self and Pop4p were also detected for Snm1p, the only unique protein subunit so far identified in RNase MRP. This observation is consistent with Snm1p and Rpr2p serving analogous functions in the two enzymes. This study provides a low-resolution map of the multisubunit architecture of the ribonucleoprotein enzyme, nuclear RNase P from S. cerevisiae.

Base Sequence↗