Biomedical subjects

Yuji Hidaka

Publications and source records attributed to Yuji Hidaka.

16 recordsLinked to original sources

PubMed2006

Crystallization and preliminary X-ray crystallographic studies of transportin 1 in complex with nucleocytoplasmic shuttling and nuclear localization fragments.

Nucleocytoplasmic transport of proteins with molar masses of larger than 60,000 is mediated by transport receptors. The transport receptor transportin1 (Trn1) transports various kinds of RNA-binding proteins such as JKTBP, hnRNP D and TAP. Trn1 was successfully cocrystallized with nucleocytoplasmic shuttling fragments of JKTBP and hnRNP D and a nuclear localization fragment of TAP. The crystal of the Trn1-JKTBP fragment complex belongs to space group P2(1)2(1)2, with unit-cell parameters a = 131.5, b =171.5, c = 68.2 angstroms. The crystals of Trn1 in complex with hnRNP D and TAP fragments are orthorhombic, space group P2(1)2(1)2(1), with unit-cell parameters a = 69.1, b = 119.1, c = 151.1 angstroms and a = 69.0, b = 119.1, c = 146.0 angstroms, respectively. The crystals diffracted to beyond 3.0, 3.2 and 2.4 angstroms resolution, respectively, using synchrotron radiation at SPring-8.

Crystallization↗

PubMed2006

Double-filtration plasmapheresis for resolution of corticosteroid resistant adult onset Still's disease.

A 45-year-old Japanese male was diagnosed with adult onset Still's disease (AOSD). High-dose corticosteroid initially resolved the illness; however, high fever, maculopalpular rashes, arthralgia, and acute pericarditis rapidly recurred, and were followed by a somnolent state without focal signs. A diagnosis of corticosteroid resistant, severe, recurrent AOSD was made, and double-filtration plasmapheresis (DFPP) was performed immediately. The somnolent state began to resolve during the first plasmapheresis procedure, and the other symptoms resolved shortly thereafter. DFPP theoretically removes monocyte-activating cytokines, such as monocyte colony-stimulating factor (M-CSF) from the circulation, and therefore may prove to be an effective treatment for corticosteroid resistant, rapidly developing cases of AOSD.

Adrenal Cortex Hormones↗

PubMed2006

Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4.

Histone arginine methylation is a posttranslational modification linked to the regulation of gene transcription. Unlike other posttranslational modifications, methylation has generally been regarded as stable, and enzymes that demethylate histone arginine residues have not been identified. However, it has recently been shown that human peptidylarginine deiminase 4 (PAD4), a Ca(2+)-dependent enzyme previously known to convert arginine residues to citrulline in histones, can also convert monomethylated arginine residues to citrulline both in vivo and in vitro. Citrullination of histone arginine residues by the enzyme antagonizes methylation by histone arginine methyltransferases and is thus a novel posttranslational modification that regulates the level of histone arginine methylation and gene activity. Here we present the crystal structures of a Ca(2+)-bound PAD4 mutant in complex with three histone N-terminal peptides, each consisting of 10 amino acid residues that include one target arginine residue for the enzyme (H3/Arg-8, H3/Arg-17, and H4/Arg-3). To each histone N-terminal peptide, the enzyme induces a beta-turn-like bent conformation composed of five successive residues at the molecular surface near the active site cleft. The remaining five residues are highly disordered. The enzyme recognizes each peptide through backbone atoms of the peptide with a possible consensus recognition motif. The sequence specificity of the peptide recognized by this enzyme is thought to be fairly broad. These observations provide structural insights into target protein recognition by histone modification enzymes and illustrate how PAD4 can target multiple arginine sites in the histone N-terminal tails.

Amino Acid Sequence↗

PubMed2006

Systemic lupus erythematosus with organic brain syndrome: serial electroencephalograms accurately evaluate therapeutic efficacy.

A 48-year-old man with systemic lupus erythematosus developed organic brain syndrome. High-dose prednisolone was ineffective, and somnolence without focal signs rapidly developed. Electroencephalogram (EEG) demonstrated a slow basic rhythm (3 Hz), but brain magnetic resonance imaging was normal. Somnolence resolved soon after performing plasma exchange (two sessions). However, memory dysfunction persisted, with EEG demonstrating mild abnormalities (7-8 Hz basic rhythm). Double-filtration plasmapheresis (three sessions) was done, followed by intravenous cyclophosphamide. Immediately after the first plasmapheresis session, memory dysfunction began to improve. After the second dose of cyclophosphamide, intellectual function resolved completely and EEG findings also normalized (basic rhythm of 10 Hz waves). Serial EEG findings precisely reflected the neurological condition and therapeutic efficacy in this patient. In contrast, protein levels in cerebrospinal fluid remained high and did not seem to appropriately reflect the neurological condition in this patient.

Azathioprine↗

PubMed2005

A case of cutaneous polyarteritis nodosa manifested by spiking high fever, arthralgia and macular eruption like adult-onset Still's disease.

A 24-year-old Japanese woman was admitted for investigation of recurrent spiking high fever associated with a macular eruption of the upper extremities associated with fever and polyarthralgia. These symptoms were self-limiting but recurrent and seemed to be consistent with a diagnosis of adult-onset Still's disease (AOSD). However, livedo reticularis was detected on the lower extremities, suggesting the presence of vasculitic disease rather than AOSD. Investigation did not reveal any evidence of visceral involvement. Skin biopsy of the affected lower extremity demonstrated a necrotizing vasculitis of small muscular artery and confirmed a diagnosis of cutaneous polyarteritis nodosa (PAN) rather than AOSD. Treatment with 30 mg of prednisolone daily improved the skin lesions and the recurrent spiking high fever and the arthralgia were resolved. PAN and AOSD are clinically similar, and discrimination may be sometimes difficult. The presence of livedo reticularis and the finding of a characteristic skin biopsy appearance may be diagnostically useful to distinguish PAN from AOSD. Indeed, the clinical features of cutaneous PAN may be more similar to AOSD than systemic PAN, and a skin biopsy may be necessary to distinguish cutaneous PAN from AOSD in some cases.

Adult↗

PubMed2005

Methylation of the guanidino group of arginine residues prevents citrullination by peptidylarginine deiminase IV.

Peptidylarginine deiminase IV (PAD IV) catalyzes the citrullination of Arg residues of proteins, such as histones. Suzuki et al. recently reported that haplotypes of the PAD IV gene are associated with susceptibility to rheumatoid arthritis. To investigate the mechanism of substrate specificity and inhibitors of PAD IV, a series of the Arg derivatives were synthesized and their reactivity to PAD IV examined. The results suggest that both imino and carboxyl groups are important in the molecular recognition of PAD IV and that methylation of the guanidino group prevents citrullination. In addition, the findings herein show that Bz-N(G)-monomethyl-Arg and Bz-N(G),N(G)-dimethyl-Arg specifically inhibit citrullination.

Arginine↗

PubMed2005

A case of polyarteritis nodosa with lesions of the superior mesenteric artery illustrating the diagnostic usefulness of three-dimensional computed tomographic angiography.

A 40-year-old Japanese man who developed upper abdominal pain, weight loss, and hypertension was diagnosed as suffering with polyarteritis nodosa (PAN) with lesions of the superior mesenteric artery (SMA). Three-dimensional computed tomographic angiography (3D-CTA) and conventional angiography revealed smooth segmental luminal narrowing of the branches of the SMA. In addition, an enhanced abdominal CT scan demonstrated diffuse thickening of the wall of the affected SMA. Treatment with high-dose corticosteroids resulted in immediate improvement of the abdominal manifestations and normalized the serum C-reactive protein levels. Furthermore, the subsequent enhanced CT and 3D-CTA revealed improvement of the wall thickening and luminal narrowing of the SMA and its branches during the treatment period. In addition to possessing the diagnostic usefulness of conventional angiography, 3D-CTA is also less invasive and facilitates the prompt and accurate diagnosis of PAN. Furthermore, thickening of the wall of medium-sized arteries evidenced by enhanced CT scan may also support a diagnosis of PAN.

Administration, Oral↗

PubMed2005

Deimination of histone H2A and H4 at arginine 3 in HL-60 granulocytes.

Interplay of various covalent modifications of histone tails has an essential role in regulation of chromatin function. Peptidylarginine deiminase (PADI) 4 deiminates protein arginine to citrulline in a Ca(2+)-dependent manner and is present in the nucleus of granulocyte-differentiated HL-60 cells. When these cells are treated with the calcium ionophore A23187, core histone deimination occurs. To determine the deimination sites of histones, histone species were purified by reverse-phase high-performance liquid chromatography (RP-HPLC) from the cells. Immunoblotting using antimodified citrulline antibody indicated that histones H2A, H3, and H4 but not H2B were deiminated. H2A and H4 were digested with Staphylococcus aureus V8 protease, and the digests were separated by RP-HPLC. Immuno dot-blotting and mass spectrometry showed that the deiminated residues were present in H2A (1-56) and H4 (1-52) regions but not in other regions. The H2A peptide (1-56) was digested with alpha-chymotrypsin, and the deiminated peptide was separated from the corresponding nondeiminated peptide by RP-HPLC. The deiminated residue was found to be limited to residues 1-23. Similarly, digestion of the H4 peptide (1-52) with endoproteinase Asp-N and separation of the deiminated peptide from the nondeiminated peptide indicated that the deiminated residue was limited to residues 1-23. Mass spectrometry of lysylendopeptidase digests of the H2A (1-23) and H4 (1-23) peptides showed that deimination occurred at arginine 3 of the N-terminal sequence Ac-SGRGK common to H2A and H4. These results suggest that PADI4 deiminates only a restricted site of target proteins in cells. Deimination of histones is discussed in relation to chromatin structure and function.

Amino Acid Sequence↗

PubMed2005

Side chain contributions to the interconversion of the topological isomers of guanylin-like peptides.

The peptide hormones guanylin and uroguanylin are ligands of the intestinal guanylyl cyclase-C (GC-C) that is involved in the regulation of epithelial water and electrolyte transport. The small peptides contain 15 and 16 amino acids, respectively, and two disulfide bonds with a 1-3/2-4 connectivity. This structural feature causes the unique existence of two topological isoforms for each peptide in an approximate 3:2 ratio, with only one of the isoforms exhibiting GC-C-activating potential. The two uroguanylin isomers can be separated by HPLC and are of sufficient stability to be studied separately at ambient temperatures while the two guanylin isomers are rapidly interconverting even at low temperatures. Both isomers show clearly distinguishable (1)H chemical shifts. To investigate the influence of certain amino acid side chains on this isomerism and interconversion kinetics, derivatives of guanylin and uroguanylin (L-alanine scan and chimeric peptides) were designed and synthesized by Fmoc solid-phase chemistry and compared by HPLC and 2D (1)H NMR spectroscopy. Amino acid residues with the most significant effects on the interconversion kinetics were predominantly identified in the COOH-terminal part of both peptides, whereas amino acids in the central part of the peptides only moderately affected the interconversion. Thus, the conformational conversion among the isomers of both peptides is under the control of a COOH-terminal sterical hindrance, providing a detailed model for this dynamic isomerism. Our results demonstrate that kinetic control of the interconversion process can be achieved by the introduction of side chains with a defined sterical profile at suitable sequence positions. This is of potential impact for the future development of GC-C peptide agonists and antagonists.

Amino Acid Sequence↗

PubMed2005

Disulfide linkages and a three-dimensional structure model of the extracellular ligand-binding domain of guanylyl cyclase C.

Guanylyl cyclase C (GC-C) is a single-transmembrane receptor that is specifically activated by endogenous ligands, including guanylin, and the exogenous ligand, heat-stable enterotoxin. Using combined HPLC separation and MS analysis techniques the positions of the disulfide linkages in the extracellular ligand-binding domain (ECD) of GC-C were determined to be between Cys7-Cys94, Cys72-Cys77, Cys101-Cys128 and Cys179-Cys226. Furthermore, a three-dimensional structural model of the ECD was constructed by homology modeling, using the structure of the ECD of GC-A as a template (van den Akker et al., 2000, Nature, 406: 101-104) and the information of the disulfide linkages. Although the GC-C model was similar to the known structure of GC-A, importantly its ligand-binding site appears to be located on the quite different region from that in GC-A.

Amino Acid Sequence↗

PubMed2005