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At least 1,099 records · Page 61Linked to original sources

PubMed2003

Cooperation of transmembrane segments during the integration of a double-spanning protein into the ER membrane.

While membrane insertion of single-spanning membrane proteins into the endoplasmic reticulum (ER) is relatively well understood, it is unclear how multi-spanning proteins integrate. We have investigated the cotranslational ER integration of a double-spanning protein that is derived from leader peptidase. Both transmembrane (TM) segments are inserted into the membrane by the Sec61 channel. While the first, long and hydrophobic TM segment (TM1) inserts into the lipid bilayer on its own, the second, shorter TM anchor (TM2) collaborates with TM1 during its integration. TM1 diffuses away from the Sec61 complex in the absence of TM2, but is close to Sec61 when TM2 arrives inside the channel. These data suggest that the exit of a weak TM segment from the Sec61 channel into the lipid phase can be facilitated by its interaction with a previously integrated strong and stabilizing TM anchor.

Amino Acid Sequence↗

PubMed1994

Analysis of membrane protein interaction: ToxR can dimerize the amino terminus of phage lambda repressor.

The ToxR protein of Vibrio cholerae is an integral membrane protein that co-ordinately regulates virulence determinant expression. ToxR directly activates the cholera toxin operon, but maximal activation is achieved in the presence of ToxS, an integral membrane protein thought to interact with ToxR periplasmic sequences. Studies that substitute alkaline phosphatase sequences for the periplasmic domain of ToxR have led to a model for ToxR activation based on dimerization and ToxS interaction. We constructed lambda-ToxR chimeric proteins using the DNA-binding domain of the phage lambda repressor, which cannot effectively dimerize by itself, to assess the ability of ToxR to form dimers in Escherichia coli. The results suggest that ToxR sequences can propagate dimerization, and that ToxS can influence the ability to dimerize.

Alkaline Phosphatase↗

PubMed2003

In vivo and in vitro assessment of baseline blood-brain barrier parameters in the presence of novel nanoparticles.

PURPOSE: Nanoparticles have advantage as CNS drug delivery vehicles given they disguise drug permeation limiting characteristics. Conflicting toxicological data, however, is published with regard to blood-brain barrier integrity and gross mortality. METHODS: To address this issue two novel nanoparticle types: "emulsifying wax/Brij 78" and "Brij 72/Tween 80 nanoparticles were evaluated in vivo for effect on cerebral perfusion flow, barrier integrity, and permeability using the in situ brain perfusion technique. Additional evaluation was completed in vitro using bovine brain microvessel endothelial cells for effect on integrity, permeability, cationic transport interactions, and tight junction protein expression. RESULTS: In the presence of either nanoparticle formulation, no overall significant differences were observed for cerebral perfusion flow in vivo. Furthermore, observed in vitro and in vivo data showed no statistical changes in barrier integrity, membrane permeability, or facilitated choline transport. Western blot analyses of occludin and claudin-1 confirmed no protein expression changes with incubation of either nanoparticle. CONCLUSIONS: The nanoparticle formulations appear to have no effect on primary BBB parameters in established in vitro and in vivo blood-brain barrier models.

Animals↗

PubMed2004

SGMD: the Soybean Genomics and Microarray Database.

The Soybean Genomics and Microarray Database (SGMD) attempts to provide an integrated view of the interaction of soybean with the soybean cyst nematode and contains genomic, EST and microarray data with embedded analytical tools allowing correlation of soybean ESTs with their gene expression profiles. SGMD provides analytical tools to mine the microarray data quickly by integrating many analysis methods within the database itself. The expression profiles of genes at time intervals during the first 8 days of nematode invasion is searchable by gene name or GenBank accession number. Recent developments include the addition of a searchable database for soybean cyst nematode ESTs and photographs of the invasion process at time points examined using microarrays. SGMD is completely accessible from the web at: http://psi081.ba.ars.usda.gov/SGMD/default.htm.

Computational Biology↗

PubMed1989

Integration of distributed cortical systems by reentry: a computer simulation of interactive functionally segregated visual areas.

A computer model based on visual cortex has been constructed to analyze how the operations of multiple, functionally segregated cortical areas can be coordinated and integrated to yield a unified perceptual response. We propose that cortical integration arises through the process of reentry--the ongoing, parallel, recursive signaling between separate maps along ordered anatomical connections. To test the efficacy of this reentrant cortical integration (RCI) model, we have carried out detailed computer simulations of 3 interconnected cortical areas in the striate and extrastriate cortex of the macaque. The simulated networks contained a total of over 222,000 units and 8.5 million connections. The 3 modeled areas, called VOR, VOC, and VMO, incorporate major anatomical and physiological properties of cortical areas V1, V3, and V5 but are vastly simplified compared with monkey visual cortex. Simulated area VOR contains both orientation and directionally selective units; simulated area VMO discriminates the direction of motion of arbitrarily oriented objects; and simulated area VOC responds to both luminance and occlusion boundaries in the stimulus. Area VOC is able to respond to illusory contours (Kanizsa, 1979) by means of the same neural architecture used for the discrimination of occlusion boundaries. This architecture also generates responses to structure-from-motion by virtue of reentrant connections from VMO to VOC. The responses of the simulated networks to these illusions are consistent with the perceptual responses of humans and other species presented with these stimuli. The networks also respond in a consistent manner to a novel illusion that combines illusory contours and structure-from-motion. The response synthesized to this combined illusion provides a strong argument supporting the need for a recursive reentrant process in the cortex. Functional integration of the simulated areas in the RCI model were found to depend upon the combined action of 3 reentrant processes: (1) conflicting responses among segregated areas are competitively eliminated, (2) outputs of each area are used by other areas in their own operations, and (3) outputs of an area are "reentered" back to itself (through lower areas) and can thus be used iteratively to synthesize responses to complex or illusory stimuli. Transection of the reentrant connections selectively abolished these integrative processes and led to failure of figural synthesis. The proposed model of reentry suggests a basis for understanding how multiple visual areas as well as other cortical areas may be integrated within a distributed system.

Animals↗

PubMed2005

Functional connection between the Clb5 cyclin, the protein kinase C pathway and the Swi4 transcription factor in Saccharomyces cerevisiae.

The rsf12 mutation was isolated in a synthetic lethal screen for genes functionally interacting with Swi4. RSF12 is CLB5. The clb5 swi4 mutant cells arrest at G(2)/M due to the activation of the DNA-damage checkpoint. Defects in DNA integrity was confirmed by the increased rates of chromosome loss and mitotic recombination. Other results suggest the presence of additional defects related to morphogenesis. Interestingly, genes of the PKC pathway rescue the growth defect of clb5 swi4, and pkc1 and slt2 mutations are synthetic lethal with clb5, pointing to a connection between Clb5, the PKC pathway, and Swi4. Different observations suggest that like Clb5, the PKC pathway and Swi4 are involved in the control of DNA integrity: there is a synthetic interaction between pkc1 and slt2 with rad9; the pkc1, slt2, and swi4 mutants are hypersensitive to hydroxyurea; and the Slt2 kinase is activated by hydroxyurea. Reciprocally, we found that clb5 mutant is hypersensitive to SDS, CFW, latrunculin B, or zymolyase, which suggests that, like the PKC pathway and Swi4, Clb5 is related to cell integrity. In summary, we report numerous genetic interactions and phenotypic descriptions supporting a close functional relationship between the Clb5 cyclin, the PKC pathway, and the Swi4 transcription factor.

Blotting, Western↗

PubMed2004

Analysis of beta-1,3-glucan assembly in Saccharomyces cerevisiae using a synthetic interaction network and altered sensitivity to caspofungin.

Large-scale screening of genetic and chemical-genetic interactions was used to examine the assembly and regulation of beta-1,3-glucan in Saccharomyces cerevisiae. Using the set of deletion mutants in approximately 4600 nonessential genes, we scored synthetic interactions with genes encoding subunits of the beta-1,3-glucan synthase (FKS1, FKS2), the glucan synthesis regulator (SMI1/KNR4), and a beta-1,3-glucanosyltransferase (GAS1). In the resulting network, FKS1, FKS2, GAS1, and SMI1 are connected to 135 genes in 195 interactions, with 26 of these genes also interacting with CHS3 encoding chitin synthase III. A network core of 51 genes is multiply connected with 112 interactions. Thirty-two of these core genes are known to be involved in cell wall assembly and polarized growth, and 8 genes of unknown function are candidates for involvement in these processes. In parallel, we screened the yeast deletion mutant collection for altered sensitivity to the glucan synthase inhibitor, caspofungin. Deletions in 52 genes led to caspofungin hypersensitivity and those in 39 genes to resistance. Integration of the glucan interaction network with the caspofungin data indicates an overlapping set of genes involved in FKS2 regulation, compensatory chitin synthesis, protein mannosylation, and the PKC1-dependent cell integrity pathway.

Antifungal Agents↗

PubMed1995

AH/PH domain-mediated interaction between Akt molecules and its potential role in Akt regulation.

The cytoplasmic serine-threonine protein kinase coded for by the c-akt proto-oncogene features a protein kinase C-like catalytic domain and a unique NH2-terminal domain (AH domain). The AH domain is a member of a domain superfamily whose prototype was observed in pleckstrin (pleckstrin homology, or PH, domain). In this communication, we present evidence that the AH/PH domain is a domain of protein-protein interaction which mediates the formation of Akt protein complexes. The interaction between c-akt AH/PH domains is highly specific, as determined by the failure of this domain to bind AKT2. The AH/PH domain-mediated interactions depend on the integrity of the entire domain. Akt molecules with deletions of the NH2-terminal portion (amino acids 11 to 60) and AH/PH constructs with deletions of the C-terminal portion of this domain (amino acids 107 to 147) fail to interact with c-akt. To determine the significance of these findings, we carried out in vitro kinase assays using Akt immunoprecipitates from serum-starved and serum-starved, platelet-derived growth factor-stimulated NIH 3T3 cells. Addition of maltose-binding protein-AH/PH fusion recombinant protein, which is expected to bind Akt, to the immunoprecipitates from serum-starved cells induced the activation of the Akt kinase.

Amino Acid Sequence↗

PubMed1998

Nuclear envelope disassembly in mitotic extract requires functional nuclear pores and a nuclear lamina.

Using sea urchin embryonic and in-vitro-assembled nuclei incubated in sea urchin mitotic extract, I provide evidence for a requirement for functional nuclear pores and a nuclear lamina for nuclear envelope disassembly in vitro. In interphase gastrula nuclei, lamin B interacts with p56, an integral protein of inner nuclear membrane cross-reacting with antibodies to human lamin B receptor. Incubation of gastrula nuclei in mitotic cytosol containing an ATP-generating system rapidly induces hyperphosphorylation of p56 and lamin B. Subsequently, p56-lamin B interactions are weakened and the two proteins segregate into distinct nuclear envelope-derived vesicles upon disassembly of nuclear membranes and of the lamina. Nuclear disassembly is accompanied by chromatin condensation. Blocking nuclear pore function with wheat germ agglutinin or antibodies to nucleoporins prevents p56 and lamin B hyperphosphorylation, nuclear membrane breakdown and lamina solubilization. These events are not rescued by permeabilization of nuclear membranes to molecules of 150, 000 Mr with lysolecithin. In-vitro-assembled nuclei containing nuclear membranes with functional pores but no lamina do not disassemble in mitotic cytosol in spite of p56 hyperphosphorylation. Nuclear import of soluble lamin B and reformation of a lamina in interphase extract restores nuclear disassembly in mitotic cytosol. The data indicate a role for functional nuclear pores in nuclear disassembly in vitro. They show that p56 hyperphosphorylation is not sufficient for nuclear membrane disassembly in mitotic cytosol and argue that the nuclear lamina plays a critical role in nuclear disassembly at mitosis.

Adenosine Triphosphate↗

PubMed2003

Ionic signaling in plant gravity and touch responses.

Plant roots are optimized to exploit resources from the soil and as each root explores this environment it will encounter a range of biotic and abiotic stimuli to which it must respond. Therefore, each root must possess a sensory array capable of monitoring and integrating these diverse stimuli to direct the appropriate growth response. Touch and gravity represent two of the biophysical stimuli that plants must integrate. As sensing both of these signals requires mechano-transduction of biophysical forces to biochemical signaling events, it is likely that they share signal transduction elements. These common signaling components may allow for cross-talk and so integration of thigmotropic and gravitropic responses. Indeed, signal transduction events in both plant touch and gravity sensing are thought to include Ca(2+)- and pH-dependent events. Additionally, it seems clear that the systems responsible for root touch and gravity response interact to generate an integrated growth response. Thus, primary and lateral roots of Arabidopsis respond to mechanical stimuli by eliciting tropic growth that is likely part of a growth strategy employed by the root to circumvent obstacles in the soil. Also, the mechano-signaling induced by encountering an obstacle apparently down-regulates the graviperception machinery to allow this kind of avoidance response. The challenge for future research will be to define how the cellular signaling events in the root cap facilitate this signal integration and growth regulation. In addition, whether other stimuli are likewise integrated with the graviresponse via signal transduction system cross-talk is an important question that remains to be answered.

Arabidopsis↗

PubMed1990

Association of spin-labeled local anesthetics at the hydrophobic surface of acetylcholine receptor in native membranes from Torpedo marmorata.

The interactions between a series of spin-labeled local anesthetic analogues and the nicotinic acetylcholine receptor (AChR) have been investigated by means of electron spin resonance (ESR) and fluorescence spectroscopy. The paramagnetic local anesthetic analogues quenched the intrinsic tryptophan fluorescence of AChR-rich membranes in an agonist-dependent manner, demonstrating a direct interaction with the AChR. The quenching efficiency was greater for the benzocaine than for the thioprocaine analogue. The protein was found to restrict directly the molecular motion of the spin-labeled analogues, as seen by the appearance of a highly anisotropic component in the ESR spectrum. The relative affinity of the population of local anesthetic probes which interacts directly with the integral protein of the AChR-rich membranes was calculated on the basis of relative association constants, Kr, determined by ESR. By comparison with the relative association constant for spin-labeled phospholipid, Kro, it was possible to differentiate between local anesthetic analogues interacting with high (Kr/Kro greater than 2), intermediate (Kr/Kro = 1.6-1.9), and low (Kr/Kro less than or equal to 1.3) specificity and to calculate the fraction of protein-associated probe in each case. Differences were observed in the presence of agonist (0.1 mM carbamylcholine) with some, but not all, of the spin-labeled derivatives. The role of the protonatable diethylammonium group in the specificity of the interaction of the procaine and thioprocaine analogues was investigated. Only in the uncharged form, or in the charged form at high ionic strength, was there a preferential association of these two local anesthetic analogues.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗

PubMed2006

The comparative toxicogenomics database: a cross-species resource for building chemical-gene interaction networks.

Chemicals in the environment play a critical role in the etiology of many human diseases. Despite their prevalence, the molecular mechanisms of action and the effects of chemicals on susceptibility to disease are not well understood. To promote understanding of these mechanisms, the Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org/) presents scientifically reviewed and curated information on chemicals, relevant genes and proteins, and their interactions in vertebrates and invertebrates. CTD integrates sequence, reference, species, microarray, and general toxicology information to provide a unique centralized resource for toxicogenomic research. The database also provides visualization capabilities that enable cross-species comparisons of gene and protein sequences. These comparisons will facilitate understanding of structure-function correlations and the genetic basis of susceptibility. Manual curation and integration of cross-species chemical-gene and chemical-protein interactions from the literature are now underway. These data will provide information for building complex interaction networks. New CTD features include (1) cross-species gene, rather than sequence, query and visualization capabilities; (2) integrated cross-links to microarray data from chemicals, genes, and sequences in CTD; (3) a reference set related to chemical-gene and protein interactions identified by an information retrieval system; and (4) a "Chemicals in the News" initiative that provides links from CTD chemicals to environmental health articles from the popular press. Here we describe these new features and our novel cross-species curation of chemical-gene and chemical-protein interactions.

Animals↗

PubMed2001

Related eIF3 subunits TIF32 and HCR1 interact with an RNA recognition motif in PRT1 required for eIF3 integrity and ribosome binding.

eIF3 binds to 40S ribosomal subunits and stimulates recruitment of Met-tRNAiMet and mRNA to the pre-initiation complex. Saccharomyces cerevisiae contains an ortholog of human eIF3 subunit p35, HCR1, whose interactions with yeast eIF3 are not well defined. We found that HCR1 has a dual function in translation initiation: it binds to, and stabilizes, the eIF3-eIF5- eIF1-eIF2 multifactor complex and is required for the normal level of 40S ribosomes. The RNA recognition motif (RRM) of eIF3 subunit PRT1 interacted simultaneously with HCR1 and with an internal domain of eIF3 subunit TIF32 that has sequence and functional similarity to HCR1. PRT1, HCR1 and TIF32 were also functionally linked by genetic suppressor analysis. We propose that HCR1 stabilizes or modulates interaction between TIF32 and the PRT1 RRM. Removal of the PRT1 RRM resulted in dissociation of TIF32, NIP1, HCR1 and eIF5 from eIF3 in vivo, and destroyed 40S ribosome binding by the residual PRT1-TIF34-TIF35 subcomplex. Hence, the PRT1 RRM is crucial for the integrity and ribosome-binding activity of eIF3.

Alleles↗

PubMed2004

A map of WW domain family interactions.

WW domains are protein modules that bind proline-rich ligands. WW domain-ligand complexes are of importance as they have been implicated in several human diseases such as muscular dystrophy, cancer, hypertension, Alzheimer's, and Huntington's diseases. We report the results of a protein array aimed at mapping all the human WW domain protein-protein interactions. Our biochemical approach integrates parallel synthesis of peptides, protein expression, and high-throughput screening methodology combined with tools of bioinformatics. The results suggest that the majority of the bioinformatically predicted WW peptide ligands and most WW domains are functional, and that only about 10% of the measured domain-ligand interactions are positive. The analysis of the WW domain protein arrays also underscores the importance of the amino acid residues surrounding the WW ligand core motifs for specific binding to WW domains. In addition, the methodology presented here allows for the rapid elucidation of WW domain-ligand interactions with multiple applications including prediction of exact WW ligand binding sites, which can be applied to the mapping of other protein signaling domain families. Such information can be applied to the generation of protein interaction networks and identification of potential drug targets. To our knowledge, this report describes the first protein-protein interaction map of a domain in the human proteome.

Amino Acid Motifs↗

PubMed1981

Effects of saccharide and salt binding on dimer-tetramer equilibrium of concanavalin A.

The effect of the binding of saccharide ligands on the reversible dimer-tetramer equilibrium on concanavalin A was studied by the high-speed sedimentation equilibrium technique. Both commercial and highly purified fragment-free concanavalin A preparations were used. In the case of the fragment-free preparation, there was no effect of the binding of alpha-methyl mannoside or alpha-methyl glucoside at 35 degrees C and at a variety of conditions of pH and ionic strength. This implies no difference in ligand binding activity between dimeric and tetrameric Con A, in contrast to an earlier report [McKenzie, G. H., & Sawyer, W. H. (1973) J. Biol. Chem. 248, 549-556]. There was a profound effect in the case of the commercial preparation. Dimers that contain hydrolyzed subunits appear to be incompetent to self-associate in the presence of alpha-methyl mannoside or alpha-methyl glycoside, while alpha-methyl galactoside, which does not bind to Con A, had no effect. The effects of very high concentrations of CaCl2 (to 2.5 m) and NaCl (60 6.2 m) were also studied. The data were analyzed by an integrated form of the Tanford extension [Tanford, C. (1969) J. Mol. Biol. 39, 539-544] of the Wyman linked function theory, which includes preferential interactions with salt and water. The integrated form allows preferential interactions to be described as the sum of salt binding and water binding. The data were well described by salt binding alone; it was unnecessary to invoke any water binding effect. The CaCl2 data did indicate that one calcium per subunit of the dimer binds to a site that is buried in the tetramer. This suggests a site on the dimmer-dimer interface which is consistent with Reeke's identification of the protomers composing the solution dimer [Reeke, G. N., Jr., Becker, J. W., & Edelman, G. M. (1975) J. Biol. Chem. 250, 1525-1547].

Calcium↗

PubMed2003

Recognition of dileucine-based sorting signals from HIV-1 Nef and LIMP-II by the AP-1 gamma-sigma1 and AP-3 delta-sigma3 hemicomplexes.

The sorting of transmembrane proteins to endosomes and lysosomes is mediated by signals present in the cytosolic tails of the proteins. A subset of these signals conform to the [DE]XXXL[LI] consensus motif and mediate sorting via interactions with heterotetrameric adaptor protein (AP) complexes. However, the identity of the AP subunits that recognize these signals remains controversial. We have used a yeast three-hybrid assay to demonstrate that [DE]XXXL[LI]-type signals from the human immunodeficiency virus negative factor protein and the lysosomal integral membrane protein II interact with combinations of the gamma and sigma1 subunits of AP-1 and the delta and sigma3 subunits of AP-3, but not the analogous combinations of AP-2 and AP-4 subunits. The sequence requirements for these interactions are similar to those for binding to the whole AP complexes in vitro and for function of the signals in vivo. These observations reveal a novel mode of recognition of sorting signals involving the gamma/delta and sigma subunits of AP-1 and AP-3.

Adaptor Protein Complex 3↗

PubMedDate not supplied

Training synergies between medical informatics and health services research: successes and challenges.

Stanford's two decades of success in linking medical informatics and health services research in both training and investigational activities reflects advantageous geography and history as well as natural synergies in the two areas. Health services research and medical informatics at Stanford have long shared a quantitative, analytic orientation, along with linked administration, curriculum, and clinical activities. Both the medical informatics and the health services research curricula draw on diverse course offerings throughout the university, and both the training and research overlap in such areas as outcomes research, large database analysis, and decision analysis/decision support. The Stanford experience suggests that successful integration of programs in medical informatics and health services research requires areas of overlapping or synergistic interest and activity among the involved faculty and, hence, in time, among the students. This is enhanced by a mixture of casual and structured contact among students from both disciplines, including social interactions. The challenges to integration are how to overcome any geographic separation that may exist in a given institution; the proper management of relationships with those sub-areas of medical informatics that have less overlap with health services research; and the need to determine how best to exploit opportunities for collaboration that naturally occur.

California↗

PubMed2005

Anatomy and neurochemistry of the pair bond.

Studies in monogamous rodents have begun to elucidate the neural circuitry underlying the formation and maintenance of selective pair bonds between mates. This research suggests that at least three distinct, yet interconnected, neural pathways interact in the establishment of the pair bond. These include circuits involved in conveying somatosensory information from the genitalia to the brain during sexual activity, the mesolimbic dopamine circuits of reward and reinforcement, and neuropeptidergic circuits involved specifically in the processing of socially salient cues. Here we present an integrated description of the interaction of these circuits in a model of pair bond formation in rodents with a discussion of the implications of these findings for evolution, individual variation, and human bonding.

Animals↗