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PubMed1976

[Molecular mechanisms of mediator secretion].

A review is presented discussing problems of transmitter localization in nerve endings, their replenishment in synaptic vesicles (SV), reuptake of transmitters and their degradation products from the synaptic cleft, the structural variations in the presynaptic membrane (pre-SM) during rest and excitation and the role of contractile proteins in the mechanism underlying transmitter secretion. A hypothesis is proposed about the universality of the mechanisms involved in transmitter release and utilization and the key role of the membrane ATP-ase system in these processes. During depolarization of the pre-SM the increase in membrane permeability is ascribed to the loosening of protein-lipid bonds and inhibition of ATP-ase activity involved in transport mechanisms. During depolarization the number of complementary contacts between SV and the pre-SM increase probably through the action of myosin-like and actin-like proteins localized on the SV and pre-SM, respectively. The release of transmitters and polypeptides is thought to be initiated by an increased concentration of Ca2+ in the synaptoplasm which induces contraction of the actomyosin-like complex. Changes in the Na-gradient brought about by the activity of Na, K-ATP-ase, are involved in the active reuptake of transmitters from the synaptic cleft. The newly-synthesized transmitters and those taken up from the synaptic cleft are stored in the SV by a Mg-ATP-ase dependent mechanism. Transmitters are stored in SV bound to acid polypeptides containing nucleotides. The presynaptic action of different neurotoxins is also discussed.

Acetylcholine↗
PubMed1994

Differential effects of monoclonal antibodies on activating transcription factor-1 and cAMP response element binding protein interactions with DNA.

Activating transcription factor-1 (ATF1) and cAMP response element binding protein (CREB) have been implicated in cAMP-, calcium-, and virus-induced transcriptional alterations. Although CREB and ATF1 share extensive homology, they appear to mediate distinct cellular functions. We investigated the effect on DNA binding and in vitro transcription of four monoclonal antibodies (mAb) that bound to domains in either the regulatory region (mAb 1 and 3) or unique regions near the DNA-binding domains (mAb 4 and 5) of ATF1.mAb 1 and 3 supershifted both ATF1 and CREB in a DNA binding assay but did not affect in vitro transcription. mAb 4 prevented ATF1-DNA binding while supershifting CREB.DNA complexes and inhibited in vitro transcription by 95% from the CRE-containing murine proliferating cell nuclear antigen promoter. mAb 5 reacted specifically with ATF1 and did not prevent DNA binding or affect in vitro transcription. The mAb 4 epitope was located within ATF1 amino acid residues 205-219, including the first 3 basic residues in the putative DNA-binding domain. Secondary structural analysis predicted that this region comprises a transition site from alpha-helix to a turn-like conformation in ATF1. The transition to turn-like motifs is predicted to occur in CREB after 5 additional residues, with a correspondingly longer alpha-helical domain. Although regulatory domains distinct from DNA binding regions are thought to account for most of the differences in activity of members of the CREB subfamily, our results suggest that small structural variations adjacent to DNA binding regions may also contribute to the distinct functional activities of ATF1 and CREB.

Activating Transcription Factor 1↗
PubMed1994

[New locus of cholinesterase (E3) expressed in human milk].

Analysis of structural variation in enzymes and other proteins of human milk revealed polymorphism of the protein exhibiting cholinesterase activity. The distribution of cholinesterase activity zones after electrophoresis of milk proteins in polyacrylamide gel differs from the pattern typical for serum cholinesterase. Samples of milk taken from 132 recently confined Russian women, which were obtained from Moscow district maternity hospital, were subjected to population analysis. Four phenotypes of the locus designated as E3, have been identified: 1-1, 2-1, 2-2 and 3-1. Preliminary visual evaluation of the electrophoretic pattern allows as to differentiate phenotypes in the following order according to enzyme activity: 2-2 > 2-1 > 3-1 > 1-1. It seems most probable that the revealed variants of cholinesterase E3 are determined by three alleles of one autosomic locus with the following frequencies: E3*1 = 0.8296; E3*2 = 0.1629 and E3*3 = 0.0075. The obtained distribution of E3 phenotypes is in good agreement with the expected one with chi 2(1) = 0.9378.

Cholinesterases↗
PubMed1994

Role of conserved cysteines of a wheat gliadin in its transport and assembly into protein bodies in Xenopus oocytes.

Following sequestration into the endoplasmic reticulum, wheat gliadin storage proteins may either be retained and packaged into protein bodies inside the organelle or be transported via the Golgi apparatus to vacuoles and condense into protein bodies at a post-endoplasmic reticulum location. To unravel the mechanism of this complex process of deposition, we expressed wild-type and mutant forms of two closely related gamma and aggregated gliadins in Xenopus oocytes. Although a considerable amount of the gamma-gliadin was secreted to the medium, its closely related aggregated gliadin was entirely retained within the oocytes. This differential secretion was largely due to structural variations in the C-terminal regions of the proteins. Retention of the wild-type aggregated and gamma-gliadins within the endoplasmic reticulum could not be explained by rapid assembly into insoluble deposits inasmuch as both proteins could diffuse rather efficiently within the organelle for several hours. To address more closely the role of the C-terminal region in the transport and assembly of the gamma-gliadin within the endoplasmic reticulum, 3 cysteine codons in this region were mutated, one at a time, to serine codons. The cysteine-replacement mutants improperly aggregated within the endoplasmic reticulum forming denser deposits compared with the wild-type protein.

Animals↗
PubMed1994

Remodeling of the transmembrane segment in human glycophorin by aberrant RNA splicing.

This paper describes the identification in S-s-U-erythrocytes of a novel glycophorin (GP), He(P2), with structural variations in both its extracellular and transmembrane domains. In the exon II-intron 2 region, a sequence transfer from GPA to GPB, probably via the mechanism of gene conversion, was associated with the induction of multiple untemplated nucleotide replacements. These changes defined the sequence for the He epitope while concomitantly abolishing GPB-associated N antigenicity. Moreover, the GPHe(P2) gene carries two splice site mutations that coordinately affect the processing of exon V coding for the transmembrane segment. The C-->G transversion at the 3' end of exon V created a cryptic acceptor splice site, whereas the G-->T transversion at the +5 position of intron 5 altered the consensus of the donor splice site. Transcript sequencing revealed that neither site was utilized in the splicing of GPHe(P2) pre-mRNA. Rather, complete skipping of exon V and subsequent joining of exon IV to exon VI caused a shift in the open reading frame, which remodeled GPHe(P2) with an elongated new hydrophobic sequence for membrane anchoring. As a result, GPHe(P2) does not display the S and U epitopes although it still contains an intact linear sequence for the two antigens. These findings illustrate how exon and intron sequences concertedly determine the specificity of in vivo splice site selection. In addition, they pinpoint the conformational dependence of the S, s, and U antigens and the importance of the hinge region for their presentation.

Amino Acid Sequence↗
PubMed1993

The multiphosphorylation domain of the phosphorylase kinase alpha M and alpha L subunits is a hotspot of differential mRNA processing and of molecular evolution.

We have cloned and sequenced human cDNAs encoding the complete phosphorylase kinase alpha subunit muscle isoform (alpha M). The predicted polypeptide is highly similar to the sequence known from rabbit muscle but lacks a major part of its multiphosphorylation domain, including the main phosphorylation site for cAMP-dependent protein kinase (PKA). Analysis of this region by reverse-transcribed polymerase chain reaction (RT-PCR) in several human and rabbit tissues demonstrates that it is subject to elaborate differential mRNA splicing. Amino acids 1012-1024 of the full-length rabbit sequence, including the major PKA phosphorylation site, and amino acids 1025-1041, which harbor at least one endogenous phosphorylation site, can be deleted from the predicted polypeptide individually or in combination. Molecules lacking one or both of these segments constitute a major part of the alpha M subunit population in many rabbit tissues and constitute the vast majority in all human tissues analyzed. Similar, tissue-dependent differential splicing events could be detected by RT-PCR in the human alpha subunit isoform from liver (alpha L). The expression of the differentially spliced alpha M subtypes differs markedly between corresponding human and rabbit tissues. Sequence divergence in this region is particularly high, not only between the muscle and liver isoforms, but also between alpha M sequences from four different animal species. Moreover, a duplication of the exon encoding the main PKA phosphorylation site was discovered in the mouse. Thus, the multiphosphorylation domain of the phosphorylase kinase alpha subunit isoforms is subject to pronounced structural variation not only between different tissues of one organism via differential splicing, but also in the course of evolution.

Alternative Splicing↗
PubMed1993

Population genetics of apolipoprotein A-4, E, and H polymorphisms in Yanomami Indians of northwestern Brazil: associations with lipids, lipoproteins, and carbohydrate metabolism.

Using isoelectric focusing and immunoblotting techniques, we screened 96 serum samples from Yanomami Indians of northwestern Brazil to determine structural variation at three apolipoprotein loci: A4, E, and H. The APO-H locus, which is commonly polymorphic in white and black samples, was found to be monomorphic. At the APO-E locus only two alleles, APOE*3 and APOE*4, rather than the three-allele polymorphism commonly seen in Caucasians, was observed. At the APO-A4 locus no example of the APOA4*2 allele, found in Caucasians, was detected. However, the frequency of the less common APOA4*4 allele was above what has been observed in any other population. We investigated the impact of genetic variation at both polymorphic loci on quantitative differences in lipids, apolipoproteins, serum glucose, glycated hemoglobin, and uric acid. Contrary to the cholesterol-elevating effect of APOE*4 reported elsewhere, in both univariate analyses and after adjustments for age, sex, weight, and height, APOE*4 was associated with about a 4% lower mean serum cholesterol. Only after adjustment was this association statistically significant. The APOE*4 allele was significantly associated with unadjusted APO-A1 and APO-E levels but not with any other dependent variable; associations with adjusted APO-A1, APO-C2, and uric acid also approached standard levels of statistical significance (p < or = 0.05). In univariate analyses the APOA4*4 allele was significantly associated with APO-B, serum glucose, percent glycated hemoglobin, and uric acid, but no significant associations were observed after dependent variables were adjusted for age, sex, weight, and height. These results support the notion that apolipoprotein distributions and their associations with lipid and carbohydrate metabolism show ethnic variability.

Adult↗
PubMed1977

[The problem of polyneuropathy in methaqualone medication].

Thirteen years after the introduction of methaqualone into therapy, investigators (namely, Finke, Spiegelberg, and Suchenwirth), by reference to individual cases, pointed out the possible development of polyneuropathies. This has not so far been confirmed despite worldwide use of the drug. Experiments on rats, which were conducted by the present authors, show a statistically significant decrease in maximum motor conduction speed, which is believed to be functional disorder. Clinical symptoms or nervous structural variations in the sense of polyneuropathy could not be observed.

Animals↗
PubMed1996

A study on macronuclear chromatin structure in Colpoda inflata (Protozoa, Ciliophora) by means of image analysis.

Resting encystment is a reversible cytodifferentiation phenomenon regularly taking place during the life cycle of Colpodidae. The encystment involves regulation of the macronuclear DNA content, accomplished via chromatin extrusion and DNA synthesis mechanisms. An analysis of macronuclear chromatin texture was carried out in Colpoda inflata logarithmically growing cells, pre-cystic cells, and increasingly aging resting cysts after Feulgen staining. Morphometric and densitometric parameters as well as Markovian chromatin texture variables were utilised for image analysis. Moreover, univariate and multivariate analyses were applied both to macronuclei and to their chromatin extrusion bodies. The results show that structural variations in chromatin appear under macronuclear functional activity conditions, suggesting a dynamic state of chromatin texture throughout a long-term resting encystment.

Animals↗
PubMed1996

Centromeric alphoid sequences are breakage prone resulting in pericentromeric inversion heteromorphism of qh region of chromosome 1.

Structural variations in the pericentromeric region of chromosome 1 are considered the norm. We characterized a chromosome 1 with an inversion by FISH-technique and suggested that the origin of pericentromeric heteromorphism is far more complex than previously suggested. It is postulated that similar to the centromeric alphoid DNA sequences of chromosome 9, chromosome 1 also possesses a "breakage prone" centromeric domain which may be a possible cause of such inversions involving the secondary constriction region.

Adult↗
PubMed1997

Bacterial adhesins: determinants of microbial colonization and pathogenicity.

Bacterial adhesins are a critical determinant of microbial colonization and are fundamental to disease pathogenesis. In this chapter, I have reviewed certain paradigms that exist with respect to structure, variation of expression, and biologic activity. No two adhesins are identical, reflecting the fact that each organism has a distinct ecological niche and is exposed to a different set of evolutionary pressures. Continued investigation is likely to identify additional paradigms and novel nuances. The hope is that we might use all this information to improve our approach to the treatment and prevention of bacterial disease.

Adhesins, Bacterial↗
PubMed1997

[Effects of genetic polymorphism of phosphoglucomutase identifiable in human milk (PGM4 locus) on the somatotype of the newborn and reproductive function of women].

The polyacrylamide gel isoelectrofocusing technique was used to examine structural variations of the human milk-expressed enzyme PGM4-locus phosphoglucomutase. Six phenotypes controlled by four alleles: PGM4*1, PGM4*2, PGM4*3, PGM4*4 with frequencies of 0.261, 0.664, 0.047, 0.028, respectively, were identified in 180 milk samples taken from Moscow Russian women in labour. The empirical distribution of the PGM4 phenotypes is in a moderate agreement with the expected one with chi 2 = 9.622; 6 d.f. (p > 0.05). Its phenotypic belonging to PGM4 1-2 and PGM4 2-2 was examined for its influence on female reproductive function and neonatal somatic type. The PGM4 1-2 phenotype was positively associated with miscarriages whereas PGM4 2-2 negatively correlated with this abnormality. If the mother had PGM4 2-2, there might be increased body dimensions (body length and mass, head and chest circumferences) in male neonates. On the contrary, PGM4 1-2 was negatively correlated with body length and mass in the newborns of both sexes. For female neonates, there was a highly significant association only with the presence of PGM4 2-2 in their mothers, namely: its presence was positively correlated with all body dimensions.

Chromosome Mapping↗
PubMed1998

Thermodynamic stability of immunoglobulins and allosteric interactions with ferritin and protein A: distinct properties of the two antibodies of IgG2a subclass.

The two anti-ferritin monoclonal antibodies of mouse IgG2a subclass, G10 and F11, are described that have similar affinity to human spleen ferritin and identical protein A-binding affinity. Antigen binding was shown to change significantly the protein A-binding parameters of the IgG2a antibodies. Antigen-induced conformational changes result in enhanced protein A-binding affinity of the G10 antibody while reduced affinity of the F11 antibody. Antigen binding does not change inherently low affinity of the anti-ferritin IgG1 antibody C5 to protein A. Differential scanning calorimetry revealed that the enthalpy and Gibbs free energy of denaturation for G10 was respectively by 19 and 29% higher than the corresponding parameters for F11. The lower structural energetics of F11 is associated with the lack of a calorimetrically revealed folding unit that may be responsible for distinct interaction between the antigen-binding and protein A-binding sites. This work provides experimental demonstration of the fact that functionally significant interactions between the two spatially remote recognition sites in antibodies of the same heavy chain isotype can be modulated by relatively small structural variations that also result in different thermodynamic stability.

Allosteric Regulation↗
PubMed1994

Nycthemeral patterns of thyroid hormones and their relationships with thyrotropin variations and sleep structure.

In order to precise the relationships between TSH, FT3, and FT4 nycthemeral variations and the relationships between thyroid hormone variations and sleep, 8 healthy young males were studied twice, once during a 24-h experiment with normal nocturnal sleep, and once during a night of sleep deprivation. The subjects received continuous enteral nutrition and remained supine during the whole experiment. Blood was sampled every 10 min for TSH, FT3, and FT4 measurements. Thyroid hormones exhibited small oscillations which were not systematically related to TSH pulses, and there was no evidence of a nycthemeral rhythm. SWS was associated with TSH declining phases, whereas awakenings were strongly associated with ascending phases of TSH variations. There was no association between sleep structure or awakenings and thyroid hormones. Sleep deprivation led to increased TSH and FT3 levels, without any variation in FT4 levels. These results demonstrate that short-term thyroid hormone variations do not only depend on the effect of TSH on thyroid secretion but also on a possible role of TSH on peripheral FT4 to FT3 conversion. Conversely, the relationships between TSH and SWS or awakenings are not mediated by thyroid hormones.

Adult↗
PubMed1988

Structural and functional variations in skeletal-muscle and scallop muscle actins.

Structural and functional properties in two striated-muscle actins, one from a vertebrate, the other from an invertebrate (scallop), were compared in relation to a smooth-muscle actin isoform (aortic actin). In spite of differences in the variable N-terminal region, the two striated-muscle isoactins showed, in contrast with aortic actin, a large structural homology revealed by proteinase-susceptibility and interaction with the myosin head. Thus the myosin head may bind to the two striated-muscle actins in constant parts of the 18-113 sequence. In contrast, antigenic reactivity of conformational epitopes of these actins strongly differentiated scallop actin from the two others. The behaviour of the scallop actin appears to be related to several amino acid substitutions located near or at functional domains such as monomer-monomer binding site, DNAase-I-dependent actin-actin binding site and actin-severing domain, which modified the polypeptide chain exposure.

Actins↗
PubMed2000

Structural conservation and variation among U5 small nuclear RNAs from trypanosomatid protozoa.

U5 snRNAs in trypanosomatid protozoa do not contain the trimethylguanosine cap structures that are often targeted in snRNA isolation procedures. As a result, the trypanosomatids are not well represented in the database of available U5 snRNA sequences. We have isolated and determined the sequence of the U5 snRNA from Crithidia fasciculata. Comparison with previously published trypanosomatid U5 snRNA sequences allows us to deduce the pattern of structural conservation and variation among these very divergent snRNA molecules.

Animals↗
PubMed2004

Study of the relationship of small variations of the molecular structure and the iron state in iron containing proteins by Mössbauer spectroscopy: biomedical approach.

This review considers the results of experimental Mössbauer studies and theoretical calculations of the effect of small variations of protein molecular structure on the iron electronic structure and stereochemistry in order to understand the proteins structural heterogeneity and functional variety. Structural changes in iron containing proteins during various diseases are also considered. These results show the relationship of the small structural variations and Mössbauer parameters of iron containing proteins and demonstrate the possibilities of Mössbauer spectroscopy to obtain new information at the molecular level in biomedical research.

Animals↗
PubMedDate not supplied

[On the regulation of the ecological community structure by a variation of the concentration ratios of resources in environment].

The possibility to regulate the structure of a community using a variational model of the ecological community was studied. The dependences of relative numbers of microorganisms on the initial ratios of resources of nutrients in environment were obtained. The potential possibility of controlling the community structure was shown. Model calculations and experimental data obtained on a community of Chlorococcales indicated that, as the ratios of resources vary, a change of the dominating species takes place.

Biodiversity↗