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PubMed1984

Structure of the variant glycoproteins and surface coat of Trypanosoma brucei.

The pathogenic African trypanosomes have a unique mechanism for antigenic variation. Each cell is covered by a surface coat consisting of about seven million essentially identical glycoprotein molecules drawn from a large repertoire of variants, each encoded by an individual gene. Amino acid sequence variation extends throughout the molecule but reduces from the amino terminus to the carboxy terminus, where certain features, especially the grouping of cysteine residues, are quite conserved. The range of diversity within the thousand or so variant glycoprotein genes that exist in each cell is large. New variants may arise instantaneously by segmental gene conversion. Variant surface glycoproteins are synthesized with amino terminal signal sequences and hydrophobic carboxy terminal tails. The tails are extraordinarily conserved. After synthesis, they are replaced by a complex glycolipid structure in which myristic (dodecanoic) acid serves to anchor the polypeptide to the surface membrane. Enzymic cleavage of myristic acid releases variant glycoproteins from the surface coat.

Amino Acid Sequence↗
PubMed1993

Structure of Met30 variant of transthyretin and its amyloidogenic implications.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary type of lethal amyloidosis involving single (or double) amino acid substitutions in the amyloidogenic protein transthyretin (TTR). The most common type of FAP (Type I, or Portuguese) is characterized by a Val-->Met substitution at position 30. The Met30 variant of TTR has been produced by recombinant methods, crystallized in a form isomorphous with native TTR, subjected to X-ray analysis and compared structurally with the wild-type protein. The comparison shows that the effect of the substitution at position 30 is transmitted through the protein core to Cys10, the only thiol group in the TTR subunit, which becomes slightly more exposed. The variant TTR molecule is otherwise in a near-native state. Use of computer graphics has shown that it is possible to model a linear aggregate of TTR molecules, each linked to the next by a pair of disulphide bonds involving Cys10 residues. Formation of these disulphide bonds involves a small number of slightly short molecular contacts with native TTR molecules, most of which are relieved in the Met30 variant. We propose this model as a possible basis for a molecular description of the FAP amyloid fibrils.

Amino Acids↗
PubMedDate not supplied

[Structure of cell-wall teichoic acids in Streptomyces roseoflavus var. roseofungini and its Nocardia-like variant].

The structure of teichoic acids was studied in the cell walls of Streptomyces roseoflavus var. roseofungini 1128 and its Nocardia-like variant 1-68 differing from the parent strain in the absence of a spore-forming aerial mycelium as well as by the fragmentation of hyphae in the substrate mycelium. The teichoic acids of the both cultures consist of a 1,3-poly(glycerophosphate) chain containing 11-13 glycerolphosphate residues which have glucosamynl units and lysine groups bound through an ester bond. These teichoic acids contain no O-acetyl groups, in contrast to the glyceroteichoic acids of actinomycetes studied earlier. The teichoic acid from the cell wall of the variant has less lysine and glucosamine then the parent strain. The content of teichoic acid in the cell wall of the parent culture is 4.5 times greater than in the wall of the variant.

Cell Wall↗
PubMed2001

Fully functional, naturally occurring and C-terminally truncated variant human immunodeficiency virus (HIV) Vif does not bind to HIV Gag but influences intermediate filament structure.

A variant human immunodeficiency virus type 1 (HIV-1) vif gene, vifA45-2, which encodes a protein lacking 19 amino acids at the C terminus but which is fully functional in supporting HIV replication in non-permissive cells has been described previously. By employing newly generated anti-VifA45 serum, further properties of VifA45 and its full-length counterpart, VifA45open, in comparison to Vif from HIV strain BH10 are reported in permissive HeLa and COS-7 cells. The results obtained using confocal microscopic localization studies and in vitro binding assays do not support a requirement for the direct interaction of HIV Gag with Vif. Furthermore and in contrast to previous conclusions, detergent solubility analyses do not demonstrate a role for the C terminus of Vif in mediating localization to the fraction containing cellular membrane proteins. Localization of Vif from HIV strain BH10 to perinuclear aggregates in a small fraction (about 10%) of transfected HeLa cells has been previously reported. The intermediate filament protein vimentin colocalizes to these structures. In contrast, VifA45 and VifA45open form perinuclear aggregates in nearly all transfected HeLa cells; vimentin as well as the cytoskeletal-bridging protein plectin, but not the microtubular protein tubulin, become relocalized to these structures. Interestingly, in COS-7 cells, all of the functional Vif proteins tested (Vif from strain BH10, VifA45 and VifA45open) predominantly localize in the cytoplasm but still induce dramatic aggregation of vimentin and plectin, i.e. in these cells the respective Vif proteins are influencing intermediate filament structure in the absence of colocalization.

Animals↗
PubMed2003

Structural features affecting variant surface glycoprotein expression in Trypanosoma brucei.

The glycosylphosphatidylinositol (GPI)-anchored variant surface glycoprotein (VSG) of Trypanosoma brucei is the most abundant GPI-anchored protein expressed on any cell, and is an essential virulence factor. To determine what structural features affect efficient expression of VSG, we made a series of mutations in two VSGs. Inserting 18 amino acids, between the amino- and carboxy-terminal domains, reduced the expression of VSG 221 to about 3% of the wild-type level. When this insertion was combined with deletion of the single carboxy-terminal subdomain, expression was reduced a further three-fold. In VSG 117, which contains two carboxy-terminal subdomains, point mutation of the intervening N-glycosylation site reduced expression about 15-fold. Deleting the most carboxy-terminal subdomain and intervening region, including the N-glycosylation site, reduced expression to 15-20% of wild type VSG, and deletion of both subdomains reduced expression to <1%. Despite their low abundance, all VSG mutants were GPI anchored on the cell surface. Our results suggest that, for a protein to be efficiently displayed on the surface of bloodstream-form T. brucei, it is essential that it contains the conserved structural motifs of a T. brucei VSG. Serum resistance-associated protein (SRA), which confers human infectivity on T. brucei, strongly resembles a VSG deletion mutant. Expression of three epitope-tagged versions of SRA in T. brucei conferred total resistance to human serum. SRA possesses a canonical GPI signal sequence, but we were unable to obtain unequivocal evidence for the presence of a GPI anchor. SRA was not released during osmotic lysis, indicating that it is not GPI anchored on the cell surface.

Amino Acid Sequence↗
PubMed2006

[FTIR characterization of the secondary structure of a staphylokinase variant (K35R) encapsulated within PLGA microspheres].

The secondary structure of a staphylokinase variant (K35R, DGR) encapsulated in poly (lactic-co-glycolic acid) (PLGA) microspheres was quantitatively examined by Fourier transform infrared (FTIR) spectroscopy. Resolution enhancement technique and Fourier deconvolution were combined with band with curve-fitting procedures to quantitate the spectral information from the amide I bands. Nine component bands were found under the broad, nearly featureless amide I bands and assigned to alpha-helix, beta-sheet, turn and irregular (random) structures. The changes of bands at 1 651 and 1 623 cm(-1) after encapsulation were discussed.

Lactic Acid↗
PubMed1998

Structural parameters for proteins derived from the atomic resolution (1.09 A) structure of a designed variant of the ColE1 ROP protein.

The crystal structure of a designed variant of the ColE1 repressor of primer (ROP) protein has been refined with SHELXL93 to a resolution of 1.09 A. The final model with 510 non-H protein atoms, 576 H atoms in calculated positions and 114 water molecules converged to a standard R factor of 10% using unrestrained blocked full-matrix refinement. For all non-H atoms six-parameter anisotropic thermal parameters have been refined. The majority of atomic vibrations have a preferred orientation which is approximately perpendicular to the bundle axis; analysis with the TLS method [Schomaker & Trueblood (1968). Acta Cryst. B24, 63-77] showed a relatively good agreement between the individual atomic displacements and a rigid-body motion of the protein. Disordered residues with multiple conformations form clusters on the surface of the protein; six C-terminal residues have been omitted from the refined model due to disorder. Part of the solvent structure forms pentagonal or hexagonal clusters which bridge neighbouring protein molecules. Some water molecules are also conserved in wild-type ROP. The unrestrained blocked full-matrix least-squares refinement yielded reliable estimates of the standard deviations of the refined parameters. Comparison of these parameters with the stereochemical restraints used in various protein refinement programs showed statistically significant differences. These restraints should be adapted to the refinement of macromolecules by taking into account parameters determined from atomic resolution protein structures.

Anisotropy↗
PubMed1997

Anatomical variants of brain structure: confused spatial relationship of the fornix to the corpus callosum and anterior commissure.

How the developing nerve fibers are guided to and able to find their target is currently a matter of research. As examples of the false guidance of axons, anatomical variants of the spatial relationship of the columna fornicis to the corpus callosum and the anterior commissure are demonstrated. In a 60 year-old female patient, some of the fibers of the genu corporis callosi were found to be entrapped by a fornix fiber bundle. The brain of a 20 year-old man showed that the unilateral anterior commissure ran posterior to the columna fornicis. These changes were clinically insignificant.

Adult↗
PubMed1990

Glycosphingolipids in insects. Chemical structures of two variants of a glucuronic-acid-containing ceramide hexasaccharide from a pupae of Calliphora vicina (Insecta: Diptera), distinguished by a N-acetylglucosamine-bound phosphoethanolamine sidechain.

The two major components of the acidic glycolipid fraction from the pupae of Calliphora vicina were isolated using high-performance liquid chromatography. The acidic moiety was identified as glucuronic acid by beta-glucuronidase cleavage and gas chromatographic analysis as the pentafluoropropionyl derivative. The structures of the carbohydrate moiety were elucidated by peracetylation, methylation, exoglycosidase cleavage, fast-atom-bombardment mass spectrometric and 1H-nuclear magnetic resonance spectroscopic analysis. The only difference between the two hexasaccharide variants was the presence, in one of them, of a between the two hexasaccharide variants was the presence, in one of them, of a phosphoethanolamine (AeP) sidechain on the third sugar of the sequence, i.e. N-acetylglucosamine. The composition of the ceramide moiety was dominated by a C20:0 fatty acid (arachidic acid) and a C14:1 sphingoid base (tetradecasphing-4-enine). The chemical structures of the two insect acidic glycosphingolipids were determined to be: GlcA(beta 1-3)Gal-(beta 1-3)GalNAc(beta 1-4)GlcNAc(beta 1-3)Man (beta 1-4)Glc(beta 1-1)Cer; GlcA(beta 1-3)Gal(beta 1-3)GalNAc(beta 1-4)[2AeP-6]-GlcNAc(beta 1-3) Man(beta 1-4)Glc(beta 1-1)Cer. Such glucuronic-acid-containing insect glycosphingolipids have been given the generic name arthrosides, with the implied synonymity to the gangliosides.

Acetylglucosamine↗
PubMed2004

Heme structures of five variants of hemoglobin M probed by resonance Raman spectroscopy.

The alpha-abnormal hemoglobin (Hb) M variants show physiological properties different from the beta-abnormal Hb M variants, that is, extremely low oxygen affinity of the normal subunit and extraordinary resistance to both enzymatic and chemical reduction of the abnormal met-subunit. To get insight into the contribution of heme structures to these differences among Hb M's, we examined the 406.7-nm excited resonance Raman (RR) spectra of five Hb M's in the frequency region from 1700 to 200 cm(-1). In the high-frequency region, profound differences between met-alpha and met-beta abnormal subunits were observed for the in-plane skeletal modes (the nu(C=C), nu(37), nu(2), nu(11), and nu(38) bands), probably reflecting different distortions of heme structure caused by the out-of-plane displacement of the heme iron due to tyrosine coordination. Below 900 cm(-1), Hb M Iwate [alpha(F8)His --> Tyr] exhibited a distinct spectral pattern for nu(15), gamma(11), delta(C(beta)C(a)C(b))(2,4), and delta(C(beta)C(c)C(d))(6,7) compared to that of Hb M Boston [alpha(E7)His --> Tyr], although both heme irons are coordinated by Tyr. The beta-abnormal Hb M variants, namely, Hb M Hyde Park [beta(F8)His --> Tyr], Hb M Saskatoon [beta(E7)His --> Tyr], and Hb M Milwaukee [beta(E11)Val --> Glu], displayed RR band patterns similar to that of metHb A, but with some minor individual differences. The RR bands characteristic of the met-subunits of Hb M's totally disappeared by chemical reduction, and the ferrous heme of abnormal subunits was no longer bonded with Tyr or Glu. They were bonded to the distal (E7) or proximal (F8) His, and this was confirmed by the presence of the nu(Fe-His) mode at 215 cm(-1) in the 441.6-nm excited RR spectra. A possible involvement of heme distortion in differences of reducibility of abnormal subunits and oxygen affinity of normal subunits is discussed.

Carbon↗
PubMed2001

SAG/ROC2/Rbx2/Hrt2, a component of SCF E3 ubiquitin ligase: genomic structure, a splicing variant, and two family pseudogenes.

We have recently cloned and characterized an evolutionarily conserved gene, Sensitive to Apoptosis Gene (SAG), which encodes a redox-sensitive antioxidant protein that protects cells from apoptosis induced by redox agents. The SAG protein was later found to be the second family member of ROC/Rbx/Hrt, a component of the Skp1-cullin-F box protein (SCF) E3 ubiquitin ligase, being required for yeast growth and capable of promoting cell growth during serum starvation. Here, we report the genomic structure of the SAG gene that consists of four exons and three introns. We also report the characterization of a SAG splicing variant (SAG-v), that contains an additional exon (exon 2; 264 bp) not present in wildtype SAG. The inclusion of exon 2 disrupts the SAG ORF and gives rise to a protein of 108 amino acids that contains the first 59 amino acids identical to SAG and a 49-amino acid novel sequence at the C terminus. The entire RING-finger domain of SAG was not translated because of several inframe stop codons within the exon 2. The SAG-v protein was expressed in multiple human tissues as well as cell lines, but at a much lower level than wildtype SAG. Unlike SAG, SAG-v was not able to rescue yeast cells from lethality in a ySAG knockout, nor did it bind to cullin-1 or have ligase activity, probably because of the lack of the RING-finger domain. Finally, we report the identification of two SAG family pseudogenes, SAGP1 and SAGP2, that share 36% or 47% sequence identity with ROC1/Rbx1/Hrt1 and 30% or 88% with SAG, respectively. Both genes are intronless with two inframe stop codons.

Alternative Splicing↗
PubMed2006

[Analysis of variant and modified structures of proteins by mass spectrometry--application for clinical laboratory test].

We have successfully applied soft ionization MS for the analysis of proteins in blood and tissues. This article is a summary of a lecture presented on March 8, 2006 in the Hall of Osaka Medical College at the time of the author's retirement from Osaka Medical College. The article addresses the detection and characterization of hemoglobin (Hb) variants, an improved reference method for HbAlc measurement, identification of variants of transthyretin (TTR) and Cu/Zn-superoxide dismutase (SOD-1) and the diagnostic application of the signals of modified forms of TTR. During the process of TTR analysis, we found unique isoforms of TTR, which showed changes of the cysteine (10th from amino terminal) residue to glycine, dehydroalanine, and S-sulfocysteine residues. Without the addition of sulfuric acid, the S-sulfonated adduct was generated, namely, sulfur was generated from the peptide or protein itself via dimer formation. These experiments suggest that transformation starts from beta-elimination of disulfide linkage to dehydroalanine and S-thiocysteine. Dehydroalanine reacts easily with H2O, generating serine, which changes to glycine. S-thiocysteine is oxidized easily to S-sulfocysteine. Such modified structures were never seen in SOD-1 and Hb in our extensive analyses by MS, although these molecules have free cysteine residue. Susceptibility to beta-elimination may depend on adjacent amino acids in the stereochemical structure of the protein. Basic amino acids located near cysteine 10, lysine residues at 9 and/or 15, may promote the reaction. As dehydroalanine in protein reacts strongly with other amino acids either in the molecule or between molecules, the reaction may generate cross-linking covalently or noncovalently, causing amyloidosis. Dehydroalanine reacts with cysteine, forming a thiazolidine ring, followed by cleavage of the peptide-bond at the N-terminal side of dehydroalanine. This type of non-enzymatic cleavage may occur in amyloidogenic precursor protein before fiber formation or in amyloid fibers.

Blood Proteins↗
PubMed1981

Immunochemical studies of human placental-type variants of alkaline phosphatase. Structural differences between the "Nagao isoenzyme" and the placental "D-variant".

Hyperimmune antisera raised against the rare FD and SD phenotypes of human placental alkaline phosphatase and the related cancer-associated Nagao isoenzyme were exhaustively absorbed with the common SS and FF phenotype enzymes conjugated to Sepharose. The antibodies so obtained had one of three specificities, determined by testing all the common phenotypes of placental alkaline phosphatase, the rare FD, SD and S-17 phenotypes, and five samples of purified cancer patient enzymes: (I) antibodies reactive with the S, D and I variant enzymes, but not with the F, 17 or Nagao enzymes; (II) antibodies reactive with the F, 17 and Nagao enzymes, but not with the S, D, and I variant enzymes; and (III) antibodies reactive with the D, 17 and Nagao enzymes and not with the S, F or I variant enzymes. Based on these data, and on the information obtained from biochemical characterization, it is argued that the Nagao isoenzyme and the D-variant are closely related but distinct enzymes. We propose a hypothetical scheme for the divergence of these two enzymes from a common ancestral gene product. In this scheme, an ancestral gene duplication resulted in two isoenzymes, one of which is completely specific to the placenta, and one of which (the "Nagao isoenzyme") has an unknown normal tissue localization, but is found in some cases of cancer. We use the term "syn-placental" to describe this latter isoenzyme, reflecting its close structural relationship to the placental isoenzyme.

Alkaline Phosphatase↗
PubMed2000

Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression.

cDNAs encoding a novel phosphodiesterase, phosphodiesterase 11A (PDE11A), were isolated by a combination of reverse transcriptase-polymerase chain reaction using degenerate oligonucleotide primers and rapid amplification of cDNA ends. Their catalytic domain was identical to that of PDE11A1 (490 amino acids) reported during the course of this study. However, the cDNAs we isolated had N termini distinct from PDE11A1, indicating two novel N-terminal variants of PDE11A. PDE11A3 cDNA encoded a 684-amino acid protein including one complete and one incomplete GAF domain in the N-terminal region. PDE11A4 was composed of 934 amino acids including two complete GAF domains and shared 630 C-terminal amino acids with PDE11A3 but had a distinct N terminus containing the putative phosphorylation sites for cAMP- and cGMP-dependent protein kinases. PDE11A3 transcripts were specifically expressed in testis, whereas PDE11A4 transcripts were particularly abundant in prostate. Recombinant PDE11A4 expressed in COS-7 cells hydrolyzed cAMP and cGMP with K(m) values of 3.0 and 1.4 microm, respectively, and the V(max) value with cAMP was almost twice that with cGMP. Although PDE11A3 showed the same K(m) values as PDE11A4, the relative V(max) values of PDE11A3 were approximately one-sixth of those of PDE11A4. PDE11A4, but not PDE11A3, was phosphorylated by both cAMP- and cGMP-dependent protein kinases in vitro. Thus, the PDE11A gene undergoes tissue-specific alternative splicing that generates structurally and functionally distinct gene products.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Genomic structure and transcript variants of the human methylenetetrahydrofolate reductase gene.

The human 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a major enzyme in the folate-dependent regulation of methionine and homocysteine concentrations. Different MTHFR mutations lead either to severe homocystinuria as a multisystem disorder or to moderate hyperhomocysteinaemia, which is a common risk factor for disorders ranging from cardiovasculopathy to spina bifida. The N-terminal part of the human MTHFR gene is incompletely characterised. We report the completed genomic structure of this gene including three novel exonic sequences on the basis of a 5'-RACE and a 4.2 kb cloned fragment of human genomic DNA. We demonstrate the existence of four MTHFR transcripts differing in their first exons. The diversity of transcripts is due to alternative transcription initiation and alternative splicing. Three putative polypeptides of 657, 698, and 680 amino acids are encoded. The novel genomic sequence described here includes putative promoter regions as suggested by the presence of regions homologue to binding sites for SP1, AP1, AP2, CAAT or GC boxes. Furthermore, we provide evidence that there are no TATA-box elements to regulate the human MTHFR gene. The results of our study render the full-length characterisation of affected alleles in severe homocystinuria and moderate hyperhomocysteinaemia due to MTHFR deficiency and provide a basis for investigating the regulation of the human MTHFR gene.

Base Sequence↗
PubMed2000

SLC7A7 genomic structure and novel variants in three Japanese lysinuric protein intolerance families.

Lysinuric protein intolerance (LPI) is a rare inherited disease caused by defective transport of the dibasic amino acids at the basolateral membranes of epithelial cells in the renal tubules and small intestine. The metabolic defect leads to brain dysfunction caused by hyperammonemia with a functional impairment of the urea cycle. Recently, mutations in the human SLC7A7 cDNA coding for y(+)LAT-1, which express dibasic amino acid transport activity, were reported to be responsible for LPI. In the present study, we examined the genomic structure of SLC7A7 by DNA sequencing of PCR products, and determined that the gene had 11 exons and 10 introns spanning about 18 kb of genomic DNA. We also identified an alternative RNA splicing at the 5' untranslated region of the SLC7A7 mRNA in human peripheral blood leukocytes, cultured lymphoblasts, and fibroblasts. As a result of mutational analysis of SLC7A7 in three Japanese LPI families, we found a nonsense mutation (R410X), a splicing mutation(911+1G>A) in intron 4, and four silent polymorphisms (201C/T, 445A/G, 784C/T, 946T/C). Identification of the genomic structure of SLC7A7 may provide a molecular basis for a genetic survey for LPI.

5' Untranslated Regions↗