[The role of protein kinase C in insulin signal transduction via adenylyl cyclase signaling mechanism].

Activation of proteinkinase C with diacylglycerol or phorbol-12-myristate-13-acetate in the rat muscle membrane or Anodonta cygnea mollusc blocks the insulin stimulating signal to adenylyl cyclase via tyrosinekinase type receptor. The same occurs with stimulating effect of biogenic amines to adenylyl cyclase via serpentine type receptor. Transduction of the inhibitory signal induced with isoproterenol to adenylyl cyclase remained unchanged in case of the proteinkinase C activation.

[Internal symmetry in nucleotide sequences of genes encoding the dolichol cycle enzymes].

In genes alg5, alg8 and swp1 of Saccharomyces cerevisiae, gpt of Schizosaccharomyces pombe and human gene alg6, encoding the dolichol cycle enzymes, a mirror type internal symmetry was found. The symmetry was detected in both complete nucleotide sequences and sequences of the first, second and third nucleotide bases of codons. In the encoding gene regions the density of single- and double-point centres of the internal symmetry for sequences of the second bases was higher in comparison with the sequences of the first and third bases of codons, whereas in the noncoding regions degrees of symmetry of the first, second and third bases sequences did not differ significantly.

[Effect of synthetic cationic peptides on activation of the adenylyl cyclase signaling system by biogenic amines in muscle tissue of molluscs and rats].

The hormone-sensitive adenylyl cyclase signaling system (ACS), made of serpentine receptor, heterotrimeric G-protein and enzyme adenylyl cyclase (AC), regulates a wide spectrum of growth and metabolic processes in the cell. Molecular mechanisms of functional coupling of ACS components still remain obscure. We examined the influence of synthetic cationic peptides Ac-Ala-His(Ala)2-His-Ala-NH2 (I), Ac-Ala-His-(Ala)3-His-(Ala)2-His-Ala-NH2 (II), and Ac-(Pro)2-His-(Ala)2-His-(Ala)3-His-(Ala)2-His-Ala-NH2 (III) on the basal AC activity and that stimulated by nonhormonal (NaF) and hormonal reagents (serotonin--molluscs, beta-isoproterenol--rats) in smooth muscles of the freshwater bivalve molluscs Anodonta cygnea and in skeletal muscles of rats.

[Role of oncogenic G-proteins in development of endocrine neoplasms].

New data available in the literature on the role of oncogenic heterotrimeric GTP-proteins (G-proteins) in endocrine tissue carcinogenesis have been analyzed. A conclusion is made that stimulatory G-proteins coded by the gsp-oncogene are a major factor of the development of some pituitary and thyroid tumors. However, the role of the other oncogenic G-proteins in tumorigenesis remains unclear.

A dual role of protein kinase C in insulin signal transduction via adenylyl cyclase signaling system in muscle tissues of vertebrates and invertebrates.

Further decoding of a novel adenylyl cyclase signaling mechanism (ACSM) of the action of insulin and related peptides detected earlier (Pertseva et al. Comp Biochem Physiol B Biochem Mol Biol 1995;112:689-95 and Pertseva et al. Biochem Pharmacol 1996;52:1867-74) was carried out with special attention given to the role of protein kinase C (PKC) in the ACSM.

Structural and functional characterization of insulin receptor substrate proteins and the molecular mechanisms of their interaction with insulin superfamily tyrosine kinase receptors and effector proteins.

The literature data on the role of IRS1/IRS2 proteins, endogenous substrates for insulin receptor tyrosine kinase, in transduction of signals generated by insulin superfamily peptides (insulin, insulin-like growth factor) were analyzed. The molecular mechanisms of the functional coupling of IRS proteins with peptide receptors possessing a tyrosine kinase activity and SH2 domain-containing proteins (phosphatidylinositol 3-kinase, Grb2 adaptor protein, protein phosphotyrosine phosphatase) were discussed. The structural and functional properties of IRS proteins (distribution of functional domains and sites for tyrosine phosphorylation; conservatism of amino acid sequences) were characterized.

[Structure-functional characteristics of heterodimeric phosphatidylinositol-3-kinase and molecular mechanisms of its conjugation with other components of the signaling system].

This review presents literary data and results of the author own studies on structural and functional characteristics of regulatory (p55/p85) and catalytic (p110) subunits of heterodimeric phosphatidylinositol-3-kinases (PI-3-kinases), and on molecular mechanisms of their functional conjugation with other signaling system components, regulated by insulin and growth factors. Various models simulating the interaction of regulatory subunits of PI-3-kinase and of their substrates (insulin receptor sustrate proteins phosphorylated on tyrosin residues) with molecules of receptors-tyrosinekinases have been considered. Mechanisms of the functional conjugation between regulatory and catalytic enzyme subunits are discussed, with special reference to a possible role of the coiled-coil interactions in this process.

[The helices with heptad regularity in cytoplasmic domains of membrane-bound adenylyl cyclases and their possible role in interaction with other adenylyl cyclase signaling system components].

The helices with heptad regularity in C1 and C2 cytoplasmic domains of membrane-bound adenylyl cyclases (AC) of mammals were identified. The most helices were localized in N-terminal and central regions of high conservative C1a and C2a subdomains of AC. The regions are responsible for regulation of enzyme functional activity.

[The role of sulfhydryl groups in functioning of components of adenylate cyclase signal system in smooth muscles of the mollusk Anodonta cygnea (effect of N-ethylmaleimide and p-chloromercuribenzoic acid)].

The alkylating agent N-ethylameimide and the sulfhydryl group blocker p-chloromercuribenzoic acid (CPMA) inhibited in dose-dependent manner both basal activity of adenylyl cyclase (AC) and its activity stimulated by non-hormonal substances (forskolin, sodium fluoride, guanylilimidodiphosphate) in smooth muscles of the freshwater bivalve mollusk Anodonta cygnea. The double increase (from 30 to 60 min) in the time of preincubation of a sarcolemmal membrane fraction with ethylmaleimide and CPMA led to an essential increase in enzyme inhibition (especially for CPMA). 50 mM SH-containing reagent beta-mercaptoethanol (ME) partially restored the AC activity, inhibited by N-ethylmaleimide and CPMA, except when these two latter reagents were in high concentrations (1-10 and 0.

[Internal symmetry of the mirror type and repeats in molecules of the membrane-bound forms of adenylate cyclase].

The analysis of mirror type internal symmetry distribution in primary structures of different types of mammalian membrane-bound adenylyl cyclases was made. The transmembrane domain clusters determining enzyme topology in membrane, a highly conservative region of cytoplasmic domains forming both catalytic and regulatory centres of adenylyl cyclases, and the functionally important regions in variable parts of their molecules (in particular, calmodulin binding regions) are shown to have symmetrical structures. These data are in conformity with a hypothesis put forward by the authors: the centres of internal symmetry may commonly either coincide with sites responsible for protein biological activity, or be spaced in the immediate vicinity of these sites.

[Cluster analysis of mirror type internal symmetry in amino acid sequences of heterotrimeric G-protein alpha-subunit superfamily].

For the identification of mirror type internal symmetry centers in amino acid sequences (AASs) the new method, named by the method of internal symmetry scanning, was developed. The method, contrary to earlier ones, can be used for analysis of large clusters of primary structures of related proteins. The internal symmetry centres, containing both one and two amino acid residues, can be identified rapidly and effectively by the method.

[Internal symmetry and repetitive sequences in the primary structure of IRS-proteins, endogenous substrates of insulin receptor].

A new method is developed for identification of mirror type internal symmetry in protein primary structures (named as method of internal symmetry scanning). As distinct from our earlier developed graphic method, the application of the new method allows, to identify enough fast and effective, symmetrical segments in proteins of any length, and to determine the type of internal symmetry centres (one or two amino acid residues). By this method the structure of IRS-proteins, endogenous substrates of tyrosine kinase receptors, was analysed.

[The identification of internal symmetry in primary structure of cytoplasmic domains of human insulin receptor beta-subunit].

The graphic method of analysis for identification of internal symmetry centres in amino acid sequences (AAS) of insulin receptor (IR) cytoplasmic 'tail' was used. The method was based on the comparison of normal and conversional sequences (AAS or sequences of amino acid codon roots). It was shown, that the regions of IR cytoplasmic domains most important for receptor functional activity possess symmetrical structure.

[Sequence homology in the primary structures of tyrosine kinase receptors of insulin superfamily and protein substrates of insulin type I and type II receptors].

Ligand-activated tyrosine kinase receptors of insulin superfamily peptides can realize the signal transduction to SH2-proteins (phosphatidylinositol 3-kinase, PI3K), protein phosphotyrosine phosphatase (PPTP), GRB2-adaptor protein in two pathways: 1) with participation of specific proteins--insulin receptor substrates 1 and 2 (IRS1/IRS2); and 2) direct interaction between receptors and SH2-proteins (without IRS-proteins). Consequently, structural related determinants, which are responsible for the interaction with SH2-proteins, must be present in the receptor and IRS molecules. The comparative analysis of amino acid sequences (AAS) of human receptors of insulin, insulin-like growth factor-I and insulin-related peptide and AAS of IRS1/IRS2 proteins allow one to identify for the first time the long homologous regions in their primary structures.

[The internal symmetry of the primary structure of the beta-subunits of the tyrosine kinase receptors in insulin superfamily peptides and its relation to their functional activity].

Using the author's original graphic method, the internal symmetry of mirror type was identified in the primary structure of beta-subunit receptor tyrosine kinases of insulin superfamily peptides (receptors of insulin, insulin-like growth factor 1 and of insulin-related peptide). The most important regions of the primary structure, determining the functional activity of receptors, were shown to have the symmetrical structure. The regions are involved in receptor autophosphorylation and kinase activity form the receptor ATP-binding site, contain N-glycosylation sites, participate in the formation of intermolecular disulfide bridges with receptor alpha-subunits, and interact with other components of the signal transduction system (in particular, with G-proteins).

[The regulatory aspects of the blood circulation in the placenta in physiological and complicated pregnancies].

New data about the development of placental circulation and the features of its regulation in normal and complicate pregnancy are considered in present review. Biochemical mechanisms leading to the dilatation of umbilical-placental circulation as well as the relaxation and contraction of placental vessels smooth muscles are discussed. It is shown that the disturbance of the balance between dilation and constriction factors being the results of injury of endothelial cells causes the spasm of uterine vessels, "delimiting" of maternal circulation from fetal one and proceeds a clinical manifestations of placental insufficiency.

[Structural elements of molecules of GTP-binding proteins and effectors mediating coupling between them].

Data available in literature on molecular mechanisms of the functional coupling of heterotrimeric G-proteins and small GTP-binding proteins (Ras-type) to effectors are analyzed. The segments of G-protein alpha-subunits which participate in formation of the effector-binding site are discussed. The induction of interaction between activated alpha-subunit and effector, following change of alpha-subunit nucleotide-binding site conformation as a result of GDP/GTP exchange is shown.