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PubMed1988

Hereditary dysfibrinogenaemia: structural and functional studies on three fibrinogen variants.

Dysfunctional fibrinogens occurring in three unrelated families were studied. Fibrinogen Erfurt I consists of B beta chains with a slightly lower molecular mass than normal. The same structural abnormality was also detected in fibrin beta chains. The variant is present in platelets too. Fibrinogen Erfurt II is characterized by the absent thrombin-induced release of FPA. With fibrinogen Berlin cleavage of the B beta chains by thrombin is slow but complete. All carriers of the three abnormal fibrinogens seem to be heterozygous for the underlying mutant gene.

Adult↗
PubMed2006

Differential expression profiles and gene structure of two tumor necrosis factor-alpha variants in Atlantic salmon (Salmo salar L.).

Here we present the gene structure and expression data on two Atlantic salmon TNF-alpha genes. Both genes are approximately 2.0kb in length and organized into four exons and three introns. The open reading frame of both genes translates into 246 amino acid putative peptides, being 91.5% identical at the amino acid level. The upstream regulatory region of both genes were amplified by inverse PCR and analyzed for putative regulatory binding sites. Variant specific gene-expression both in vitro and in vivo revealed that the two variants are differentially regulated. TNF-alpha2 is the dominant variant throughout the experimental period following LPS stimulation of TO-cells. The picture was different in head kidney tissue following vaccination of Atlantic salmon with an experimental multivalent oil-based vaccine. TNF-alpha2 was the most dominant transcript in the non-stimulated controls and in the early phase. A shift from TNF-alpha2 to TNF-alpha1 was however seen, and from day 12 the TNF-alpha1 was most abundant transcript. Implications of variant specific gene-expression are discussed.

Amino Acid Sequence↗
PubMed1999

A series of bioactivity-variant neurotoxins from scorpion Buthus martensii Karsch: X-ray crystal structure and functional implications.

Three bioactivity-variant neurotoxins, BmK M1, M4, and M8, have been purified from venom of the Chinese scorpion Buthus martensii Karsch. They possess distinct toxic activity on mice in vivo with different electrostatic properties. The relative toxicities of BmK M1, M4, and M8 are 13.3:2.5:1, which interestingly correspond to their respective pI values, ranging from basic to acidic, of 9.01, 7.53, and 5.30, respectively. In addition, the X-ray crystal structure of BmK M8, which is acidic and 1100 times less active than the most potent and basic alpha-toxin AaH II, have been determined at 1.85 A resolution and analyzed in detail. In combination with information from chemical modifications and site-directed mutagenesis, the structural comparisons and sequence alignments suggest a multisite binding mode for toxin-receptor interactions, and three "toxic regions" with relevance to the binding process, including Face A, Face B, and Site C. Face A is featured in the presence of several aromatic residues and may be more essential for the binding; Face B may contribute to the high efficacy of the binding process, on which substitution by acidic residues could weaken the toxic activity; Site C is probably involved in binding site specificity. The main residues involved in these regions will be discussed.

Amino Acid Sequence↗
PubMed1976

[Conditions for the self-organization of submicroscopic structures from mycelial extracts of the "fructose" variant of Actinomyces roseflavus var. roseofungini].

Self-organization of various submicroscopic formations, such as "tubes", "ribbons", etc. differing in ultrastructure and containing a polyenic antibiotic was observed in acetone extracts of the mycelium of the "fructose" variant of Actinomyces roseoflavus var. roseofungini. Conditions for separate isolation of the above structures are described. Concentration of the extract and the ratio of the volumes of water added to the extract are determinant for the process of self-organization. A possibility of reorganization of the tubular structures into the ribbon-like ones and vice versa is shown.

Cell Fractionation↗
PubMedDate not supplied

Active cross-protection induced by a recombinant baculovirus expressing chimeric infectious bursal disease virus structural proteins.

The VP2 structural gene encoded in the large genomic segment A of the variant GLS strain of infectious bursal disease virus (IBDV) was modified to encode a neutralization epitope (B69), found only on classic strains of IBDV. A chimeric cDNA clone of the large segment A, encoding VP3, VP4, and the modified variant IBDV VP2 structural proteins, was expressed in a recombinant baculovirus. The chimeric protein expressed was assessed with a panel of neutralizing monoclonal antibodies (MAbs), and it contained not only all previously MAb-defined GLS variant strain epitopes but also the B69 neutralization epitope found on classic IBDV strains. Complete active protection was afforded to specific-pathogen-free chickens by a subunit chimeric vaccine against virulent challenge with the classic IM and STC strains, as well as against the variant E/Del and GLS IBDV strains. Compared with a previously tested recombinant subunit vaccine, which incorporated unmodified baculovirus-expressed large-segment A GLS proteins, the recombinant chimeric subunit vaccine resulted in markedly improved active cross-protection against classic IBDV challenge.

Animals↗
PubMed2003

Structural studies of hydrogen bonds in the high-affinity streptavidin-biotin complex: mutations of amino acids interacting with the ureido oxygen of biotin.

An elaborate hydrogen-bonding network contributes to the tight binding of biotin to streptavidin. The specific energetic contributions of hydrogen bonds to the biotin ureido oxygen have previously been investigated by mapping the equilibrium and activation thermodynamic signatures of N23A, N23E, S27A, Y43A and Y43F site-directed mutants [Klumb et al. (1998), Biochemistry, 37, 7657-7663]. The crystal structures of these variants in the unbound and biotin-bound states provide structural insight into the energetic alterations and are described here. High (1.5-2.2 A) to atomic resolution (1.14 A) structures were obtained and structural models were refined to R values ranging from 0.12 to 0.20. The overall folding of streptavidin as described previously has not changed in any of the mutant structures. Major deviations such as side-chain shifts of residues in the binding site are observed only for the N23A and Y43A mutations. In none of the mutants is a systematic shift of biotin observed when one of the hydrogen-bonding partners to the ureido oxygen of biotin is removed. Recent thermodynamic studies report increases of DeltaDeltaG(o) of 5.0-14.6 kJ mol(-1) for these mutants with respect to the wild-type protein. The decreasing stabilities of the complexes of the mutants are discussed in terms of their structures.

Amino Acid Substitution↗
PubMed2004

Crystallographic studies on structural features that determine the enzymatic specificity and potency of human angiogenin: Thr44, Thr80, and residues 38-41.

Human angiogenin (Ang) is a potent inducer of blood vessel formation and is a member of the pancreatic ribonuclease superfamily. Its enzymatic activity is unusually weak and biased toward cleavage after cytidine nucleotides. As part of an ongoing investigation into the structural basis of Ang's characteristic activity, we have determined the crystal structures of three Ang variants having novel activity. (i) The structure of T44D-Ang indicates that Asp44 can participate directly in pyrimidine binding and that the intrinsic hydrogen-bonding capability of this residue largely governs the pyrimidine specificity of this variant. Unexpectedly, the mutation also causes the most extensive disruption of the C-terminus seen in any Ang variant thus far. This allows the side chain of Arg101 to penetrate the B(1) site, raising the possibility that it participates in substrate binding as occurs in ribonuclease 4. (ii) The structure of T80A-Ang supports the view that Thr80 plays little role in maintaining the obstructive conformation of the C-terminus and that its participation in a hydrogen bond with Thr44 selectively weakens the interaction between Thr44 and N3 of cytosine. (iii) ARH-II is an angiogenin/RNase A chimera in which residues 38-41 of Ang are replaced with the corresponding residues (38-42) of RNase A. Its structure suggests that the guest segment influences catalysis by subtle means, possibly by reducing the pK(a) of the catalytic lysine. The loss of angiogenic activity is not attributable to disruption of known cell-binding or nuclear translocation sites but may be a consequence of the chimera's enhanced ribonucleolytic activity.

Alanine↗
PubMed2006

Crystal structure of the Orf virus NZ2 variant of vascular endothelial growth factor-E. Implications for receptor specificity.

Mammalian vascular endothelial growth factors constitute a family of polypeptides, vascular endothelial growth factor (VEGF)-A, -B, -C, -D and placenta growth factor (PlGF), that regulate blood and lymphatic vessel development. VEGFs bind to three types of receptor tyrosine kinases, VEGF receptors 1, 2, and 3, that are predominantly expressed on endothelial and some hematopoietic cells. Pox viruses of the Orf family encode highly related proteins called VEGF-E that show only 25-35% amino acid identity with VEGF-A but bind with comparable affinity to VEGFR-2. The crystal structure of VEGF-E NZ2 described here reveals high similarity to the known structural homologs VEGF-A, PlGF, and the snake venoms Vammin and VR-1, which are all homodimers and contain the characteristic cysteine knot motif. Distinct conformational differences are observed in loop L1 and particularly in L3, which contains a highly flexible GS-rich motif that differs from all other structural homologs. Based on our structure, we created chimeric proteins by exchanging selected segments in L1 and L3 with the corresponding sequences from PlGF. Single loop mutants did not bind to either receptor, whereas a VEGF-E mutant in which both L1 and L3 were replaced gained affinity for VEGFR-1, illustrating the possibility to engineer receptor-specific chimeric VEGF molecules. In addition, changing arginine 46 to isoleucine in L1 significantly increased the affinity of VEGF-E for both VEGF receptors.

Amino Acid Sequence↗
PubMed2006

Solution structure of mouse Cripto CFC domain and its inactive variant Trp107Ala.

We report here for the first time the solution structures at pH 3 and pH 6 of the synthetic CFC domain of mouse Cripto and of the point mutated variant W107A that is unable to bind to the Alk4 Cripto receptor. NMR data confirm that the CFC domain has a C1-C4, C2-C6, C3-C5 disulfide pattern and show that structures are rather flexible and globally extended, with three noncanonical antiparallel strands. His104 and Trp107 side chains protrude from a protein edge and are strongly exposed to solvent, supporting previous evidence of direct involvement in receptor binding. On the opposite molecule side, several nonpolar residues are gathered, forming a large hydrophobic patch that supposedly acts as interface with the cell membrane or the adjacent EGF-like domain. A second hydrophilic patch surrounding His104 and Trp107 is present only in the wild type variant, suggesting a possible involvement in modulating Alk4 recognition.

Amino Acid Sequence↗
PubMed1988

Nonrandom involvement of chromosome 4 in the progression of rat prostatic cancer.

Owing to progression of the original spontaneous Dunning R-3327 rat prostatic cancer, a large series of transplantable prostatic tumors have been isolated that differ widely in their histological degree of differentiation, growth rate, androgen sensitivity, and metastatic ability. Using these parameters as criteria, the full spectrum of disease progression is represented within this Dunning system of rat prostatic cancers, ranging from slow-growing, well-differentiated, androgen-sensitive, nonmetastatic forms to fast-growing, anaplastic, androgen-independent, highly metastatic forms. Cytogenetic analysis of the two least progressionally advanced Dunning cancers (i.e., histologically well-differentiated, slow-growing, nonmetastatic variants) demonstrated no structural or numerical chromosomal aberration, suggesting that the initial development of prostatic cancer may not require detectable cytogenetic changes. In contrast, all 16 of the progressionally more advanced Dunning variants analyzed had a series of characteristic structural and/or numerical chromosomal aberrations that minimally involved chromosome 4. This nonrandom involvement of chromosome 4 was consistently observed regardless of whether the karyotype of the cancer was near-diploid or hyperaneuploid, suggesting that chromosome 4 aberrations are specifically involved in the progression of rat prostatic cancer. In addition, all four variants that were highly metastatic had, besides aberration of chromosome 4, structural aberrations involving chromosomes 1, 2, and 11. Of the 14 variants that did not have a high metastatic ability, only two had a similar aberrations involving chromosomes 1, 2, 4, and 11, suggesting that these specific chromosomal aberrations may be necessary, albeit not sufficient, for a high metastatic ability of rat prostatic cancers.

Adenocarcinoma↗
PubMed2002

Morpho-functional evaluation of osteomeatal complex in chronic sinusitis by coronal CT.

The objective was to determine whether or not there exists a clinical-radiological correlation in chronic sinusitis of anterior paranasal sinus and to quantitatively evaluate the importance of osteomeatal complex structures and anatomic variants in chronic sinusitis etiopathology. We analyzed 208 nasal fossae with high-resolution and low-irradiation coronal computed tomography. The following inclusion criteria we established: one case control and one control group. We considered any chronic thickness of sinusal mucosal as a radiological indicator of chronic sinusitis. We evaluated the mucosal thickness of internal, external, superior and inferior maxillary walls, the addition of four maxillary walls and the maximal mucosal thickness in frontal sinus and anterior ethmoidal cells. We also obtained 15 parameters of osteomeatal complex structures and anatomical variants in each nasal fossa, and we correlated them statistically with chronic sinusitis radiological indicators. Uncinate process length is the only anatomic element from which we have been able to obtain a statistically significant cut point between case and control groups, but only with a sensitivity of 51.6%, specificity of 71.2%, positive predictive value of 74.2%, and negative predictive value of 47.9%. No association of radiological parameters exists that can explain chronic sinusitis.

Adult↗
PubMed1991

Structural characterization of the asparagine-linked oligosaccharides from Trypanosoma brucei type II and type III variant surface glycoproteins.

The complete primary structures of the major Asn-linked oligosaccharides from the type II variant surface glycoproteins (VSGs), MITat 1.2 and MITat 1.7, and the type III VSG, MITat 1.5, were determined using a combination of exo- and endoglycosidase digestions, methylation analysis, acetolysis, and 500 MHz 1H NMR spectroscopy. Each variant contained classical branched oligomannose-type and biantennary complex oligosaccharides, a proportion of the latter substituted with terminal alpha(1-3)-linked galactose residues, the first report of the presence of this epitope in Trypanosoma brucei. In addition both the type II variants contained relatively large amounts of the unusual small oligomannose-type oligosaccharides, Man4GlcNAc2 and Man3GlcNAc2, and a diverse array of novel branched poly-N-acetyllactosamine oligosaccharides, similar but not identical to those from mammalian glycoproteins. These latter structures were also partially substituted with terminal alpha(1-3)-linked galactose residues. Glycosylation in the type II variants showed site specificity in that the poly-N-acetyllactosamine and Man(9-5)GlcNAc2 oligosaccharides were located exclusively at Asn-glycosylation site 1 very close to the C terminus, whereas the Man(4-3)GlcNAc2 and biantennary complex oligosaccharides were located exclusively at site 2. This is the first report of the presence of poly-N-acetyllactosamine oligosaccharides in protozoa.

Asparagine↗
PubMed2002

[Structural and functional analysis of 2.2 kb spliced variant of hepatitis B virus genomes isolated from liver tissues from hepatocellular carcinoma patients].

BACKGROUND: To study the structure and function of 2.2 kb spliced variant of HBV genome from liver tissues of hepatocellular carcinoma patients. METHODS: HBV genomes were amplified by using PCR from paired hepatocellular carcinoma tissues and peritumor tissues. The 3.2 kb full-length HBV genome and 2.2 kb spliced variant were separately cloned and sequenced. Hep G2 cells were co-transfected with full-length HBV DNA and 2.2 kb spliced variant, and after transfection, HBV DNAs from intracellular core particles were harvested and specific primers were used in PCR to evaluate the interactions between spliced variant and full-length counterpart in replication. RESULTS: Semi-quantification by scanning density showed that 2.2 kb spliced variant was present in all tumor and peri-tumor samples studied. Sequence analyes revealed that the 5 terminus packaging signal for pregenomic and X and PreC/C genes were retained. When full-length HBV DNA was co-transfected with 2.2 kb, the replication signal of 3.2 kb HBV genome was increased 3-7 times. CONCLUSIONS: The 2.2 kb HBV spliced variant was present in liver tissues, and relative content was higher in tumor tissues than that in the peri-tumor tissues. This spliced variant could enhance the replication of full-length HBV genome, which suggested the possible role of the variant in the pathogenesis of development of hepatocellular carcinoma.

Adult↗
PubMed1999

Crystal structures of Escherichia coli glycerol kinase variant S58-->W in complex with nonhydrolyzable ATP analogues reveal a putative active conformation of the enzyme as a result of domain motion.

Escherichia coli glycerol kinase (GK) displays "half-of-the-sites" reactivity toward ATP and allosteric regulation by fructose 1, 6-bisphosphate (FBP), which has been shown to promote dimer-tetramer assembly and to inhibit only tetramers. To probe the role of tetramer assembly, a mutation (Ser58-->Trp) was designed to sterically block formation of the dimer-dimer interface near the FBP binding site [Ormo, M., Bystrom, C., and Remington, S. J. (1998) Biochemistry 37, 16565-16572]. The substitution did not substantially change the Michaelis constants or alter allosteric regulation of GK by a second effector, the phosphocarrier protein IIAGlc; however, it eliminated FBP inhibition. Crystal structures of GK in complex with different nontransferable ATP analogues and glycerol revealed an asymmetric dimer with one subunit adopting an open conformation and the other adopting the closed conformation found in previously determined structures. The conformational difference is produced by a approximately 6.0 degrees rigid-body rotation of the N-terminal domain with respect to the C-terminal domain, similar to that observed for hexokinase and actin, members of the same ATPase superfamily. Two of the ATP analogues bound in nonproductive conformations in both subunits. However, beta, gamma-difluoromethyleneadenosine 5'-triphosphate (AMP-PCF2P), a potent inhibitor of GK, bound nonproductively in the closed subunit and in a putative productive conformation in the open subunit, with the gamma-phosphate placed for in-line transfer to glycerol. This asymmetry is consistent with "half-of-the-sites" reactivity and suggests that the inhibition of GK by FBP is due to restriction of domain motion.

Actins↗
PubMed2004

Structure-function correlations derived from faster variants of a RNA ligase deoxyribozyme.

We previously reported the in vitro selection of several Mg2+-dependent deoxyribozymes (DNA enzymes) that synthesize a 2'-5' RNA linkage from a 2',3'-cyclic phosphate and a 5'-hydroxyl. Here we subjected the 9A2 deoxyribozyme to re-selection for improved ligation rate. We found two new DNA enzymes (7Z81 and 7Z48) that contain the catalytic core of 7Q10, a previously reported small deoxyribozyme that is unrelated in sequence to 9A2. A third new DNA enzyme (7Z101) is unrelated to either 7Q10 or 9A2. The new 7Z81 and 7Z48 DNA enzymes have ligation rates over an order of magnitude higher than that of 7Q10 itself and they have additional sequence elements that correlate with these faster rates. Our findings provide insight into structure-function relationships of catalytic nucleic acids.

Base Sequence↗
PubMed2001

Analysis of iceA genotypes in South African Helicobacter pylori strains and relationship to clinically significant disease.

BACKGROUND: South African Helicobacter pylori isolates are characterised by the universal presence of cagA but have differences in vacuolating cytotoxin gene (vacA) alleles which correlate with clinically significant disease. However, the candidate virulence marker gene iceA has not been investigated. AIM: To characterise the genetic organisation and heterogeneity of iceA genotypes in different South African clinical isolates. PATIENTS AND METHODS: We studied H pylori strains isolated from 86 dyspeptic patients (30 with peptic ulcer disease (PUD), 19 with distal gastric adenocarcinoma (GC), and 37 with non-erosive gastritis) for the presence of iceA1 or iceA2 genes, and for differences in the genetic organisation of iceA2 by polymerase chain reaction, Southern hybridisation analysis, and sequencing. RESULTS: Genetic analysis of iceA1 demonstrated significant homology (92-95%) with the USA type strain 26695 and probably functions as a transcriptional regulator, while a novel variant (iceA2D') of iceA2 and marked differences in predicted protein secondary structure of the iceA2 protein were defined. iceA1 was detected in 68% and iceA2 in 80% of all clinical isolates. Although approximately 40% of patients had both strains, a higher prevalence (p< 0.01) of GC patients were infected with iceA1 isolates which were invariably vacA s1/iceA1 (p< 0.005 v gastritis). Isolates from PUD patients were distinguished by the structurally altered iceA2D variant (53%; p<0.03 v gastritis) while the iceA2C variant distinguished isolates from patients with gastritis alone (67%; p< 0.005 v PUD). CONCLUSION: In this study, an association between iceA1 and GC was noted while differences in variants of iceA2 differentiated between PUD and gastritis alone. Combination analyses of iceA genotypes and vacA alleles supported these associations.

Adenocarcinoma↗
PubMedDate not supplied

[The primary structure of the hemagglutinin gene of strain A/Riga/9977/86--a drift variant of influenza virus A(H3N2)].

The hemagglutinin gene primary structure of influenza virus A/Riga/9977/86 (H3N2) belonging to the "Coen/84" antigenic subgroup was determined by primer sequencing. A comparative analysis confirmed that the reversions of amino acids in the late stages of the H3 influenza virus subtype antigenic drift became more frequent and the antigenic variants remained in epidemic circulation longer. The possible role of some mutations is discussed.

Antigenic Variation↗
PubMed1992

Transesophageal echocardiography: normal variants and mimickers.

An accurate diagnosis of cardiac pathology using TEE is contingent upon the ability to recognize and differentiate normal cardiac structures and normal variants from pathologic conditions. We describe several normal cardiac structures commonly imaged using TEE of the atria, interatrial septum, aorta, valves, and extracardiac spaces that may mimic diverse pathologic states, such as intracardiac tumor and thrombus, valvular vegetations, mitral and tricuspid valve prolapse, atherosclerotic plaque, and aortic dissection. Methods to aid in the differentiation of normal cardiac structures from pathology are offered.

Aorta↗