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Hirano A.,Japan National Institute of Advanced Industrial Science and Technology | Kameda T.,Tokyo Science and Industrial Research Institute | Shinozaki D.,University of Tsukuba | Arakawa T.,Alliance Protein Laboratories | Shiraki K.,University of Tsukuba
Journal of Physical Chemistry B | Year: 2013

We have previously demonstrated that arginine increases the solubility of aromatic compounds that have poor water solubility, an effect referred to as the "arginine-assisted solubilization system (AASS)". In the current study, we utilized a molecular dynamics simulation to examine the solubilization effects of arginine on caffeic acid, which has a tendency to aggregate in aqueous solution. Caffeic acid has a hydrophobic moiety containing a π-conjugated system that includes an aromatic ring and a hydrophilic moiety with hydroxyl groups and a carboxyl group. While its solubility increases at higher pH values due to the acquisition of a negative charge, the solubility was greatly enhanced by the addition of 1 M arginine hydrochloride at any pH. The results of the simulation indicated that the caffeic acid aggregates were dissociated by the arginine hydrochloride, which is consistent with the experimental data. The binding free energy calculation for two caffeic acid molecules in an aqueous 1 M arginine hydrochloride solution indicated that arginine stabilized the dissociated state due to the interaction between its guanidinium group and the π-conjugated system of the caffeic acid. The binding free energy of two caffeic acid molecules in the arginine hydrochloride solution exhibited a local minimum at approximately 8 Å, at which the arginine intervened between the caffeic acid molecules, causing a stabilization of the dissociated state of caffeic acid. Such stabilization by arginine likely led to the caffeic acid solubilization, as observed in both the experiment and the MD simulation. The results reported in this paper suggest that AASS can be attributed to the stabilization resulting from the intervention of arginine in the interaction between the aromatic compounds. © 2013 American Chemical Society.

Nomura M.,University of Tokyo | Nomura M.,Albert Ludwigs University of Freiburg | Nakagawa J.,University of Tokyo | Kage Y.,University of Tokyo | And 4 more authors.
Applied Physics Letters | Year: 2015

Thermal phonon transport in silicon nanowires (Si NWs) and two-dimensional phononic crystal (2D PnC) nanostructures was investigated by measuring thermal conductivity using a micrometer-scale time-domain thermoreflectance. The impact of nanopatterning on thermal conductivity strongly depends on the geometry, specularity parameter, and thermal phonon mean free path (MFP) distribution. Thermal conductivities for 2D PnC nanostructures were found to be much lower than that for NWs with similar characteristic length and surface-to-volume ratio due to stronger phonon back scattering. In single-crystalline Si, PnC patterning has a stronger impact at 4 K than at room temperature due to a higher specularity parameter and a longer thermal phonon MFP. Nanowire patterning has a stronger impact in polycrystalline Si, where thermal phonon MFP distribution is biased longer by grain boundary scattering. © 2015 AIP Publishing LLC.

Hirano A.,University of Tsukuba | Kameda T.,Tokyo Science and Industrial Research Institute | Arakawa T.,Alliance Protein Laboratories | Shiraki K.,University of Tsukuba
Journal of Physical Chemistry B | Year: 2010

The poor aqueous solubility of drug substances hampers their broader applications. This paper describes a de novo strategy to increase the aqueous solubility of drug substances using an arginine-assisted solubilization system (AASS) with alkyl gallates as model drug substances. Solubility experiments of alkyl gallates showed that arginine greatly increases the aqueous solubility of different alkyl gallates, whose aqueous solubilities differ widely. In contrast, lysine showed marginal effects on alkyl gallates solubility. Molecular dynamic simulation indicated a greater interaction of arginine with alkyl gallates than that of lysine, which reflects favorable interaction between the guanidinium group of arginine and the aromatic ring of alkyl gallates. Such interaction apparently disrupts association of alkyl gallate molecules, leading to solubilization. These results indicate AASS as a promising approach to solubilize poorly soluble drug substances containing aromatic ring structures. © 2010 American Chemical Society.

Komatsu M.,Tokyo Metropolitan Institute of Medical Science | Komatsu M.,Japan Science and Technology Corporation | Kurokawa H.,Tohoku University | Waguri S.,Fukushima Medical University | And 18 more authors.
Nature Cell Biology | Year: 2010

Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes. © 2010 Macmillan Publishers Limited. All rights reserved.

Sekine Y.,University of Tokyo | Hatanaka R.,University of Tokyo | Watanabe T.,University of Tokyo | Sono N.,University of Tokyo | And 9 more authors.
Molecular Cell | Year: 2012

Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H2O2-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5. © 2012 Elsevier Inc.

Nemoto W.,Tokyo Science and Industrial Research Institute | Nemoto W.,Tokyo Denki University | Toh H.,Tokyo Science and Industrial Research Institute
BMC Structural Biology | Year: 2012

Background: The detection of conserved residue clusters on a protein structure is one of the effective strategies for the prediction of functional protein regions. Various methods, such as Evolutionary Trace, have been developed based on this strategy. In such approaches, the conserved residues are identified through comparisons of homologous amino acid sequences. Therefore, the selection of homologous sequences is a critical step. It is empirically known that a certain degree of sequence divergence in the set of homologous sequences is required for the identification of conserved residues. However, the development of a method to select homologous sequences appropriate for the identification of conserved residues has not been sufficiently addressed. An objective and general method to select appropriate homologous sequences is desired for the efficient prediction of functional regions. Results: We have developed a novel index to select the sequences appropriate for the identification of conserved residues, and implemented the index within our method to predict the functional regions of a protein. The implementation of the index improved the performance of the functional region prediction. The index represents the degree of conserved residue clustering on the tertiary structure of the protein. For this purpose, the structure and sequence information were integrated within the index by the application of spatial statistics. Spatial statistics is a field of statistics in which not only the attributes but also the geometrical coordinates of the data are considered simultaneously. Higher degrees of clustering generate larger index scores. We adopted the set of homologous sequences with the highest index score, under the assumption that the best prediction accuracy is obtained when the degree of clustering is the maximum. The set of sequences selected by the index led to higher functional region prediction performance than the sets of sequences selected by other sequence-based methods. Conclusions: Appropriate homologous sequences are selected automatically and objectively by the index. Such sequence selection improved the performance of functional region prediction. As far as we know, this is the first approach in which spatial statistics have been applied to protein analyses. Such integration of structure and sequence information would be useful for other bioinformatics problems. © 2012 Nemoto and Toh; licensee BioMed Central Ltd.

Daiyasu H.,Osaka University | Nemoto W.,Tokyo Denki University | Toh H.,Tokyo Science and Industrial Research Institute
Frontiers in Microbiology | Year: 2012

Chemokine receptors (CKRs) function in the inflammatory response and in vertebrate homeostasis. Decoy and viral receptors are two types of CKR homologs with modified functions from those of the typical CKRs. The decoy receptors are able to bind ligands without signaling. On the other hand, the viral receptors show constitutive signaling without ligands. We examined the sites related to the functional difference. At first, the decoy and viral receptors were each classified into five groups, based on the molecular phylogenetic analysis. A multiple amino acid sequence alignment between each group and the CKRs was then constructed. The difference in the amino acid composition between the group and the CKRs was evaluated as the Kullback-Leibler (KL) information value at each alignment site.The KL information value is considered to reflect the difference in the functional constraints at the site. The sites with the top 5% of KL information values were selected and mapped on the structure of a CKR. The comparisons with decoy receptor groups revealed that the detected sites were biased on the intracellular side. In contrast, the sites detected from the comparisons with viral receptor groups were found on both the extracellular and intracellular sides. More sites were found in the ligand binding pocket in the analyses of the viral receptor groups, as compared to the decoy receptor groups. Some of the detected sites were located in the GPCR motifs. For example, the DRY motif of the decoy receptors was often degraded, although the motif of the viral receptors was basically conserved. The observations for the viral receptor groups suggested that the constraints in the pocket region are loose and that the sites on the intracellular side are different from those for the decoy receptors, which may be related to the constitutive signaling activity of the viral receptors.© 2012 Daiyasu, Nemoto and Toh.

Anufriev R.,University of Tokyo | Maire J.,University of Tokyo | Maire J.,Tokyo Science and Industrial Research Institute | Nomura M.,University of Tokyo | Nomura M.,Japan Science and Technology Agency
Physical Review B - Condensed Matter and Materials Physics | Year: 2016

We investigate the impact of various phonon-scattering mechanisms on the in-plane thermal conductivity of suspended silicon thin films with two-dimensional periodic arrays of holes, i.e., phononic crystal (PnC) nanostructures. A large amount of data on the PnC structures with square, hexagonal, and honeycomb lattices reveals that the thermal conductivity is mostly determined by the surface-to-volume ratio. However, as the characteristic size of the structure is reduced down to several tens of nanometers, thermal conductivity becomes independent of the surface-to-volume ratio, lattice type, and other geometrical parameters, being controlled solely by the distance between adjacent holes (neck size). © 2016 American Physical Society.

Nemoto W.,Tokyo Science and Industrial Research Institute | Fukui K.,Tokyo Science and Industrial Research Institute | Toh H.,Tokyo Science and Industrial Research Institute
Journal of Receptors and Signal Transduction | Year: 2011

The G protein Coupled Receptor (GPCR) superfamily is one of the most important pharmaceutical targets. Studies of GPCRs have long been performed under the assumption that GPCRs function as monomers. However, recent studies have revealed that many GPCRs function as homo- and/or hetero-dimers or higher-order oligomeric molecular complexes. As a result, information about GPCR oligomerization is rapidly accumulating, although the molecular mechanisms of oligomerization are not fully understood. A comprehensive collection of information about oligomerization would accelerate investigations of the molecular mechanisms of GPCRs'' oligomerization and involvement in signaling. Hence, we have developed a database, G protein coupled Receptor Interaction Partners DataBase (GRIPDB), which provides information about GPCR oligomerization. The entries in the database are divided into two sections: (I) Experiment Information section and (II) Prediction Information section. The Experiment Information section contains (I-i) experimentally indentified GPCR oligomers and their annotations, and (I-ii) experimentally suggested interfaces for the oligomerization. Since the number of experimentally suggested interfaces is limited, the entries in the Prediction Information section have been introduced to provide information about the oligomerization interfaces predicted by our computational method. The experimentally suggested or computationally predicted interfaces are displayed by 3D graphics, using GPCRs with available coordinates. The information in the GRIPDB, especially that about the interfaces, is useful to investigate the molecular mechanisms of signal transduction via GPCR oligomerization. The GRIPDB is available on the web at the following URL: http://grip.cbrc.jp/GDB/index.html. © 2011 Informa Healthcare USA, Inc.

Uchikoga N.,Japan Biological Informatics Consortium | Uchikoga N.,Tokyo Science and Industrial Research Institute | Hirokawa T.,Tokyo Science and Industrial Research Institute
BMC Bioinformatics | Year: 2010

Background: Protein-protein docking for proteins with large conformational changes was analyzed by using interaction fingerprints, one of the scales for measuring similarities among complex structures, utilized especially for searching near-native protein-ligand or protein-protein complex structures. Here, we have proposed a combined method for analyzing protein-protein docking by taking large conformational changes into consideration. This combined method consists of ensemble soft docking with multiple protein structures, refinement of complexes, and cluster analysis using interaction fingerprints and energy profiles.Results: To test for the applicability of this combined method, various CaM-ligand complexes were reconstructed from the NMR structures of unbound CaM. For the purpose of reconstruction, we used three known CaM-ligands, namely, the CaM-binding peptides of cyclic nucleotide gateway (CNG), CaM kinase kinase (CaMKK) and the plasma membrane Ca2+ATPase pump (PMCA), and thirty-one structurally diverse CaM conformations. For each ligand, 62000 CaM-ligand complexes were generated in the docking step and the relationship between their energy profiles and structural similarities to the native complex were analyzed using interaction fingerprint and RMSD. Near-native clusters were obtained in the case of CNG and CaMKK.Conclusions: The interaction fingerprint method discriminated near-native structures better than the RMSD method in cluster analysis. We showed that a combined method that includes the interaction fingerprint is very useful for protein-protein docking analysis of certain cases. © 2010 Uchikoga and Hirokawa; licensee BioMed Central Ltd.

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