Journal articles: 'Insulin chain-B'

1

Csaba, G., and P. Kovács. "Influence of imprinting with A and B chains of insulin on binding and functional changes in tetrahymena." Bioscience Reports 10, no. 5 (October 1, 1990): 431–36. http://dx.doi.org/10.1007/bf01152289.

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Insulin and its A and B chain increased the quantity of intracellular PAS-positive material (glycogen) in tetrahymena, whereas the combined A+B chains decreased it. Imprinting—previous interaction—with insulin, its A and B chains in themselves and with the A+B chain increased the hormone binding capacity of tetrahymena, but the functional effect of imprinting (storage or breakdown of glycogen) showed a different tendency with insulin and A+B chain on the one hand, and A chain and B chain on the other. Since the imprinting potential of a molecule promotes the induction of receptor formation, the fact remains that both component chains of insulin were able to act as potential imprinters, although the A chain was superior to the B chain in this respect throughout, and combined treatment with the A+B chain ultimately induced the formation of a similar binding site as insulin itself.

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2

Davies, J. G., A. V. Muir, and R. E. Offord. "Identification of some cleavage sites of insulin by insulin proteinase." Biochemical Journal 240, no. 2 (December 1, 1986): 609–12. http://dx.doi.org/10.1042/bj2400609.

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In a previous study [Muir, Offord & Davies (1986) Biochem. J. 237, 631-637] the chromatographic and electrophoretic behaviour of a major labelled fragment in the degradation of tritiated insulins by insulin proteinase were used to locate the probable sites of cleavage which had produced this fragment. In order to define these cleavage sites more precisely, authentic markers for the fragments which would be produced by cleavages at, or adjacent to, the most likely sites have now been synthesized. These markers were compared with labelled fragments of the A- and B-chains of insulin produced by insulin proteinase. The results, together with those of our previous study, show that in order to produce the observed major labelled fragment, the enzyme must have cleaved the insulin A-chain between leucine-A13 and tyrosine-A14 and the insulin B-chain between serine-B9 and histidine-B10. In addition, a minor component was observed in the labelled B-chain fragment which corresponded to a cleavage either between histidine-B10 and leucine-B11 or between leucine-B11 and valine-B12.

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3

YUAN, Ying, Zhao-Hui WANG, and Jian-Guo TANG. "Intra-A chain disulphide bond forms first during insulin precursor folding." Biochemical Journal 343, no. 1 (September 24, 1999): 139–44. http://dx.doi.org/10.1042/bj3430139.

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In this study, we investigated the folding pathway of insulin precursor and compared it with that of insulin-like growth factor I (IGF-I). The intra-A chain disulphide bond was found to form early in insulin precursor folding, whereas the corresponding disulphide bond in IGF-I formed late. Intra-A chain disulphide-bond deleted [A6, A11-Ser] proteins, including proinsulin, insulin, and A chain, were employed for this investigation. Under the same conditions the recombination yield of insulin from S-sulphonates of native A and B chains was 22%, while the yield of [A6, A11-Ser] insulin from S-sulphonates of [A6, A11-Ser] A chain and native B chains was only approx. 7%. This indicated that the intra-A chain disulphide bond may serve to stabilize the A chain folding intermediate so as to facilitate the correct recognition and pairing with the B chain. Time courses of oxidation of reduced insulin A chains, reduced A and B chains, and reduced proinsulins showed that the intra-A chain disulphide bond formed first during insulin precursor folding. The formation of intra-A chain disulphide bond further accelerated the formation of the other two inter-chain disulphide bonds. The time course of helix structure formation of insulin A chains also indicated that the intra-A chain disulphide bond formed first, and could stabilize partially folded A chain helix structure. The rate of intra-A chain disulphide bond formation was almost the same as that for both helix structure formation and insulin molecule formation, indicating that the formation of the intra-A chain disulphide bond was the rate limiting step for the folding of insulin precursor.

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4

MARON, RUTH, NANCY S. BLOGG, MALU POLANSKI, WAYNE HANCOCK, and HOWARD L. WEINER. "Oral Tolerance to Insulin and the Insulin B-Chain." Annals of the New York Academy of Sciences 778, no. 1 (February 1996): 346–57. http://dx.doi.org/10.1111/j.1749-6632.1996.tb21142.x.

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5

Miller, G. G., J. F. Hoy, and J. W. Thomas. "Insulin B chain functions as an effective competitor of antigen presentation via peptide homologies present in the thymus." Journal of Experimental Medicine 169, no. 6 (June 1, 1989): 2251–56. http://dx.doi.org/10.1084/jem.169.6.2251.

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The B chain of mammalian insulins contains appropriately spaced amino acids that predict recognition by T cells. However, all T cell clones from an HLA-DR1, Dw6 diabetic donor recognize epitopes associated with the A chain, and the B chain was found to inhibit these responses. Effective intramolecular competition at the level of the APC, not a direct effect on the T cell, is responsible for the inhibition. Insulin B chain contains two clusters of amino acid homology with the TCR beta chain and B chain peptides lacking these clusters do not compete for antigen presentation. A hole in the repertoire for T cells that recognize this portion of the insulin molecule may arise in the thymus by deletion of T cells that recognize similar peptides.

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6

Budi, Akin, F. Sue Legge, Herbert Treutlein, and Irene Yarovsky. "Electric Field Effects on Insulin Chain-B Conformation." Journal of Physical Chemistry B 109, no. 47 (December 2005): 22641–48. http://dx.doi.org/10.1021/jp052742q.

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7

PAYNOVICH, RICHARD C., and FREDERICK H. CARPENTER. "OXIDATION OF THE SULFHYDRYL FORMS OF INSULIN A-CHAIN AND B-CHAIN." International Journal of Peptide and Protein Research 13, no. 2 (January 12, 2009): 113–21. http://dx.doi.org/10.1111/j.1399-3011.1979.tb01858.x.

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8

Klimontov, Vadim Valer'evich, and Natalya Evgen'evna Myakina. "Insulin glargine: pharmacokinetic and pharmacodynamic basis of clinical effect." Diabetes mellitus 17, no. 4 (October 17, 2014): 99–107. http://dx.doi.org/10.14341/dm2014499-107.

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Glargine became the first long-acting insulin analogue. Glargine was designed to meet basal insulin requirements throughout the day with a single injection. Pharmacokinetics of insulin glargine is characterized by biotransformation into metabolites M1 and M2 that transforms the B chain of glargine so it is similar to the B chain of human insulin. Plasma concentrations of active M1 and M2 metabolites have no pronounced peaks during the day, resulting in lower glucose variability and hypoglycaemia risk when compared with NPH insulin. The metabolic activities of M1 and M2 metabolites are similar to the effect of glargine, whereas the mitogenic effects of these metabolites do not exceed the effect of human insulin. Insulin glargine shows a higher affinity for the insulin-like growth factor-1 (IGF-1) receptor when compared with human insulin. Glargine has no proliferative effect in vivo owing to its rapid conversion into metabolites. Pharmacokinetic and pharmacodynamic variability of glargine is comparable to other insulins. These characteristics are important for the clinical efficacy and safety of glargine.

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9

Nedjar, S., G. Humbert, J. Y. Le Deaut, and G. Linden. "Specificity of chymosin on immobilized bovine B-chain insulin." International Journal of Biochemistry 23, no. 3 (January 1991): 377–81. http://dx.doi.org/10.1016/0020-711x(91)90122-4.

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10

Chrudinová, Martina, Lenka Žáková, Aleš Marek, Ondřej Socha, Miloš Buděšínský, Martin Hubálek, Jan Pícha, Kateřina Macháčková, Jiří Jiráček, and Irena Selicharová. "A versatile insulin analog with high potency for both insulin and insulin-like growth factor 1 receptors: Structural implications for receptor binding." Journal of Biological Chemistry 293, no. 43 (September 13, 2018): 16818–29. http://dx.doi.org/10.1074/jbc.ra118.004852.

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Insulin and insulin-like growth factor 1 (IGF-1) are closely related hormones involved in the regulation of metabolism and growth. They elicit their functions through activation of tyrosine kinase–type receptors: insulin receptors (IR-A and IR-B) and IGF-1 receptor (IGF-1R). Despite similarity in primary and three-dimensional structures, insulin and IGF-1 bind the noncognate receptor with substantially reduced affinity. We prepared [d-HisB24, GlyB31, TyrB32]-insulin, which binds all three receptors with high affinity (251 or 338% binding affinity to IR-A respectively to IR-B relative to insulin and 12.4% binding affinity to IGF-1R relative to IGF-1). We prepared other modified insulins with the aim of explaining the versatility of [d-HisB24, GlyB31, TyrB32]-insulin. Through structural, activity, and kinetic studies of these insulin analogs, we concluded that the ability of [d-HisB24, GlyB31, TyrB32]-insulin to stimulate all three receptors is provided by structural changes caused by a reversed chirality at the B24 combined with the extension of the C terminus of the B chain by two extra residues. We assume that the structural changes allow the directing of the B chain C terminus to some extra interactions with the receptors. These unusual interactions lead to a decrease of dissociation rate from the IR and conversely enable easier association with IGF-1R. All of the structural changes were made at the hormones' Site 1, which is thought to interact with the Site 1 of the receptors. The results of the study suggest that merely modifications of Site 1 of the hormone are sufficient to change the receptor specificity of insulin.

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11

CONLON, J. Michael, Elizabeth S. CAVANAUGH, Dennis C. MYNARCIK, and Jonathan WHITTAKER. "Characterization of an insulin from the three-toed amphiuma (Amphibia: Urodela) with an N-terminally extended A-chain and high receptor-binding affinity." Biochemical Journal 313, no. 1 (January 1, 1996): 283–87. http://dx.doi.org/10.1042/bj3130283.

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Insulin was isolated from an extract of the pancreas of a urodele, the three-toed amphiuma (Amphiuma tridactylum), and its primary structure established as Ala-Arg-Gly-Ile-Val-Glu-Gln-Cys-Cys-His10-Asn-Thr-Cys-Ser-Leu-Asn-Gln-Leu-Glu-Asn20-Tyr-Cys-Asn for the A-chain and Ile-Thr-Asn-Gln-Tyr-Leu-Cys-Gly-Ser-His10-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly20-Asp-Arg-Gly-Phe-Phe-Tyr-Ser-Pro-Lysfor the B-chain. The N-terminus of the A-chain is extended by two amino acids (Ala-Arg) relative to all other known insulins suggesting an anomalous pathway of post-translational processing in the region of the C-peptide/A-chain junction of proinsulin. In common with chicken and Xenopus insulins, which contain a HisA8, amphiuma insulin was more potent (approx. 5-fold) than porcine insulin in inhibiting the binding of [125I-TyrA14]insulin to the soluble human insulin receptor from transfected 293EBNA cells (an adenovirus-transformed human kidney cell line). This result is consistent with previous data showing that insulin analogues extended at GlyA1 by uncharged groups have reduced binding affinity whereas high affinity is preserved in analogues extended by basic amino acid residues.

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12

Schwartz, Gerald P., G. Thompson Burke, Maqsood Sheikh, Lin Zong, and Panayotis G. Katsoyannis. "Synthesis of an insulin-like compound consisting of the B chain of insulin and an A chain corresponding to the A and D domains of human insulin-like growth factor I." Collection of Czechoslovak Chemical Communications 53, no. 11 (1988): 2920–35. http://dx.doi.org/10.1135/cccc19882920.

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We report the synthesis and biological evaluation of a two-chain, disulfide-linked, insulin-like compound in which the A chain amino acid sequence corresponds to that of the A- and D-domains of human insulin-like growth factor I (IGF-I), and the B chain is that of bovine insulin. The compound displays reduced insulin-like activity, but considerably increased growth-promoting activity relative to insulin, and is not recognized by IGF carrier proteins. These data confirm some of our earlier conclusions regarding the role of the A-, B- and D-domains in the expression of the biological profile of IGF-I: The A-domain, but not the B- or D-domain is associated with the growth-promoting activity of IGF-I; the B-domain, but not the A- or D-domain, contains determinants for the recognition of IGF carrier proteins; and the D-domain acts to supress insulin-like activity in IGF-I.

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13

Dupradeau, F. Y., G. Le Flem, T. Richard, J. P. Monti, H. Oulyadi, and Y. Prigent. "A new B-chain mutant of insulin: comparison with the insulin crystal structure and role of sulfonate groups in the B-chain structure." Journal of Peptide Research 60, no. 1 (December 5, 2008): 56–64. http://dx.doi.org/10.1034/j.1399-3011.2002.02990.x.

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14

Tang, J. G., C. C. Wang, and C. L. Tsou. "Formation of native insulin from the scrambled molecule by protein disulphide-isomerase." Biochemical Journal 255, no. 2 (October 15, 1988): 451–55. http://dx.doi.org/10.1042/bj2550451.

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The formation of native insulin either from scrambled insulin or from the separated A chain and B chain S-sulphonates by protein disulphide-isomerase was demonstrated with yields of 20-30% as measured by h.p.l.c. analysis, receptor binding and stimulation of lipogenesis. The h.p.l.c. profile of the reaction products shows that, among all the possible isomers containing both chains, the native hormone is by far the predominating product and consequently the most stable under certain conditions.

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15

Zachayus, J. L., S. Khan, and C. Plas. "Sequential insulin degradation in cultured fetal hepatocytes in relation to chloroquine-dependent events." American Journal of Physiology-Endocrinology and Metabolism 271, no. 3 (September 1, 1996): E417—E425. http://dx.doi.org/10.1152/ajpendo.1996.271.3.e417.

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Insulin cellular degradation was studied in cultured 18-day-old fetal rat hepatocytes in the presence and absence of insulin degradation inhibitors that decrease the glycogenic response to insulin. After cell incubation with 3 nM [125I]A14 or -B26 insulin, hormone degradation products associated with cells or present in the medium were analyzed by high-performance liquid chromatography. Within cells, four components containing intact [125I]A14 insulin A-chain and part of the B-chain (A1-A4, according to increasing retention times) were found together with two [125I]B26 insulin B-chain COOH-terminal fragments (B1 and B2). Medium degradation intermediates comprised B1 and B2 but not A1-A4. Cellular insulin fragments A3 and B2 exhibited a maximal transient accumulation after 2 min, whereas the others increased progressively to plateau after 10 min. Chloroquine inhibited the formation of A1, A2, and B1 by 70-80%, whereas that of A3, A4, and B2 was not significantly affected. N-ethylmaleimide and bacitracin, two inhibitors of insulin-degrading enzyme (IDE), decreased the formation of chloroquine-dependent cellular peptides. Thus cell-associated insulin degradation implied primarily two cleavages in B-chain near the COOH-terminus, the one sensitive to chloroquine and IDE inhibitors occurring after endosomal segregation of insulin and its receptor.

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16

Liwen, Niu, Liang Dongcai, Zhang Fugui, and Zhu Minhui. "STUDIES ON THE CONFORMATIONAL ENERGIES OF INSULIN B-CHAIN HELIX." Acta Physico-Chimica Sinica 3, no. 06 (1987): 561–64. http://dx.doi.org/10.3866/pku.whxb19870601.

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17

Hong, Dong-Pyo, and Anthony L. Fink. "Independent Heterologous Fibrillation of Insulin and Its B-Chain Peptide." Biochemistry 44, no. 50 (December 2005): 16701–9. http://dx.doi.org/10.1021/bi051658y.

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18

Jensen, Peter E. "Immunogenicity of B chain in insulin responder and nonresponder mice." Cellular Immunology 130, no. 1 (October 1990): 129–38. http://dx.doi.org/10.1016/0008-8749(90)90167-p.

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19

Legge, F. S., A. Budi, H. Treutlein, and I. Yarovsky. "Protein flexibility: Multiple molecular dynamics simulations of insulin chain B." Biophysical Chemistry 119, no. 2 (January 2006): 146–57. http://dx.doi.org/10.1016/j.bpc.2005.08.002.

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20

Muir, A., R. E. Offord, and J. G. Davies. "The identification of a major product of the degradation of insulin by ‘insulin proteinase’ (EC 3.4.22.11)." Biochemical Journal 237, no. 3 (August 1, 1986): 631–37. http://dx.doi.org/10.1042/bj2370631.

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We have studied a major product in the degradation of insulin by insulin proteinase (EC 3.4.22.11). Semisynthetic [[3H]PheB1]insulin and [[3H]GlyA1]insulin were used in the experiments. The structure of the fragment was deduced by observing the chromatographic and electrophoretic migration of the label both before and after further digestion of the fragment with proteinases of known specificity, with and without additional treatment by performic acid. Ambiguities were resolved by studying the behaviour of authentic fragments of known structure, isolated and characterized after digestion of intact insulin by proteinases of known specificity. We conclude that a major product in the degradation of insulin by insulin proteinase consists of a truncated section of the A chain, joined by the disulphide bridge B7-A7 to a truncated section of the B chain. The A-chain fragment consists most probably of residues A1-A13, and the B-chain fragment consists most probably of residues B1-B9. The similarity between this fragment and that found by other workers when insulin is degraded by intact hepatocytes is significant in the light of proposals that insulin proteinase is a possible participant in the physiological degradation of insulin by target cells.

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21

Bajaj, M., T. L. Blundell, R. Horuk, J. E. Pitts, S. P. Wood, L. K. Gowan, C. Schwabe, A. Wollmer, J. Gliemann, and S. Gammeltoft. "Coypu insulin. Primary structure, conformation and biological properties of a hystricomorph rodent insulin." Biochemical Journal 238, no. 2 (September 1, 1986): 345–51. http://dx.doi.org/10.1042/bj2380345.

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Insulin from a hystricomorph rodent, coypu (Myocaster coypus), was isolated and purified to near homogeneity. Like the other insulins that have been characterized in this Suborder of Rodentia, coypu insulin also exhibits a very low (3%) biological potency, relative to pig insulin, on lipogenesis in isolated rat fat-cells. The receptor-binding affinity is significantly higher (5-8%) in rat fat-cells, in rat liver plasma membranes and in pig liver cells, indicating that the efficacy of coypu insulin on receptors is about 2-fold lower than that of pig insulin. The primary structures of the oxidized A- and B-chains were determined, and our sequence analysis confirms a previous report [Smith (1972) Diabetes 21, Suppl. 2, 457-460] that the C-terminus of the A-chain is extended by a single residue (i.e. aspartate-A22), in contrast with most other insulin sequences, which terminate at residue A21. In spite of a large number of amino acid substitutions (relative to mammalian insulins), computer-graphics model-building studies suggest a similar spatial arrangement for coypu insulin to that for pig insulin. The substitution of the zinc-co-ordinating site (B10-His----Gln) along with various substitutions on the intermolecular surfaces involved in the formation of higher aggregates are consistent with the observation that this insulin is predominantly ‘monomeric’ in nature. The c.d. spectrum of coypu insulin is relatively similar to those of casiragua insulin and of bovine insulin at low concentration.

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22

Mohan, James F., Shirley J. Petzold, and Emil R. Unanue. "Register shifting of an insulin peptide–MHC complex allows diabetogenic T cells to escape thymic deletion." Journal of Experimental Medicine 208, no. 12 (November 7, 2011): 2375–83. http://dx.doi.org/10.1084/jem.20111502.

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In nonobese diabetic (NOD) mice, two sets of autoreactive CD4+ T cells recognize the B:9–23 segment of the insulin B chain. One set, type A, recognizes insulin presented by antigen-presenting cells (APCs). These T cells are highly deleted in the thymus. The second set, type B, does not recognize insulin protein but reacts with soluble B chain peptide. This set is not deleted in the thymus but is activated in the islets of Langerhans. In this study, we examine the specificity of these two types of T cells. The protein-reactive set recognizes the stretch of residues 13–21 of the insulin B chain. The set reactive to peptide only recognizes the stretch from residues 12–20. A single amino acid shift of the B chain peptide bound to I-Ag7 determines whether T cells recognize peptides generated by the processing of insulin, and consequently their escape from thymic purging. Biochemical experiments indicate that peptides bound in the 13–21 register interact more favorably with I-Ag7 than peptides that bind in the 12–20 register. Thus, self-reactive T cells can become pathogenic in the target organ where high concentrations of antigen and/or differences in intracellular processing present peptides in registers distinct from those found in the thymus.

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23

Yao, Zhi-Ping, Zong-Hao Zeng, Hong-Min Li, Ying Zhang, You-Min Feng, and Da-Cheng Wang. "Structure of an insulin dimer in an orthorhombic crystal: the structure analysis of a human insulin mutant (B9 Ser→Glu)." Acta Crystallographica Section D Biological Crystallography 55, no. 9 (September 1, 1999): 1524–32. http://dx.doi.org/10.1107/s0907444999008562.

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The structure of human insulin mutant B9 (Ser→Glu) was determined by an X-ray crystallographic method at 2.5 Å resolution with an R factor of 0.165 under non-crystallographic restraints. The crystals were grown at low pH (<3.8) and belong to the orthorhombic P212121 space group with unit-cell dimensions a = 44.54, b = 46.40, c = 51.85 Å and one dimer per asymmetric unit without further aggregation. The structure in this crystal form can be regarded as a model for a discrete insulin dimer and displays the following features compared with the structure of 2Zn insulin. (i) The overall dimer is expanded and more symmetric. The two A chains are about 2 Å more distant from each other, while the two B chains are about 0.8 Å further apart. Both monomers are more similar to molecule 1 than molecule 2 of the 2Zn insulin dimer. (ii) The dimer structure is stabilized by protonation and neutralization of the carboxyl groups at lower pH and, in addition, by formation of a hydrogen-bond network among the side chains of residues GluB9, HisB13 and HisB10 on the dimer-forming surface of both monomers, resulting from a structural rearrangement. (iii) The B-chain amino-terminal segment is in an open state (O state), i.e. a state different from the well known R and T states found in the insulin hexamer. In the O state, the B-chain N-terminal segment is in an extended conformation and is detached from the rest of the molecule. This conformational state has also been observed in the monomeric crystal structure of despentapeptide (B26–B30) and desheptapeptide (B24–B30) insulin, as well as in the solution structure of an engineered insulin monomer. It suggests that the O state may be the characteristic conformation of insulin in lower aggregation forms and may be relevant to the formation of insulin fibrils. In addition, based on the crystallization process, the smallest possible building blocks of insulin crystal are also discussed.

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24

SEABRIGHT, Paul J., and Geoffrey D. SMITH. "The characterization of endosomal insulin degradation intermediates and their sequence of production." Biochemical Journal 320, no. 3 (December 15, 1996): 947–56. http://dx.doi.org/10.1042/bj3200947.

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Insulin degradation within isolated rat liver endosomes was studied in vitro with the aid of three 125I-insulin isomers specifically labelled at tyrosine (A14, B16 and B26). Chloroquine and 1,10-phenanthroline were used to minimize insulin proteolysis during endosome preparation, whereas the manipulation of endosomal processing of insulin in vitro by Co2+ ions (to activate) and 1,10-phenanthroline (to inhibit) permitted the study of degradation intermediates and their time-dependent production. Structural and kinetic analysis of intermediates isolated from both intra- and extra-endosomal compartments allowed the determination of major cleavage sites and the probable sequence of proteolytic events. It was found that 125I-tyrosine is the ultimate labelled degradation product of all iodo-insulin isomers, suggesting that endosomal proteases are able to degrade insulin to the level of its constituent amino acids. 125I-tyrosine was also the only radiolabelled product able to cross the endosomal membrane. Intra-endosomal insulin degradation proceeds via two inter-related cleavage routes after metalloendoprotease cleavage of the B-chain. One pathway results from an initial cleavage in the centre region of the B-chain (B7–19), probably at B14-15, whereas the major route results from a cleavage at B24-25. B24-25 cleavage removes the B-chain C-terminal hexapeptide (B25–30), which is subsequently cleaved by an aminopeptidase activity to produce first the pentapeptide B26–30 and then 125I-tyrosine. The isolation of intact radiolabelled A-chain from the degradation of 125I-[A14]-insulin suggests that further degradation of proteolytic intermediates containing cleaved B-chain proceeds via interchain disulphide reduction. The A-chain is then processed by several cleavages, one of which occurs at A13-14.

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25

Majercik, M. H., and L. Y. W. Bourguignon. "Insulin-induced myosin light-chain phosphorylation during receptor capping in IM-9 human B-lymphoblasts." Biochemical Journal 252, no. 3 (June 15, 1988): 815–23. http://dx.doi.org/10.1042/bj2520815.

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We have examined further the interaction between insulin surface receptors and the cytoskeleton of IM-9 human lymphoblasts. Using immunocytochemical techniques, we determined that actin, myosin, calmodulin and myosin light-chain kinase (MLCK) are all accumulated directly underneath insulin-receptor caps. In addition, we have now established that the concentration of intracellular Ca2+ (as measured by fura-2 fluorescence) increases just before insulin-induced receptor capping. Most importantly, we found that the binding of insulin to its receptor induces phosphorylation of myosin light chain in vivo. Furthermore, a number of drugs known to abolish the activation properties of calmodulin, such as trifluoperazine (TFP) or W-7, strongly inhibit insulin-receptor capping and myosin light-chain phosphorylation. These data imply that an actomyosin cytoskeletal contraction, regulated by Ca2+/calmodulin and MLCK, is involved in insulin-receptor capping. Biochemical analysis in vitro has revealed that IM-9 insulin receptors are physically associated with actin and myosin; and most interestingly, the binding of insulin-receptor/cytoskeletal complex significantly enhances the phosphorylation of the 20 kDa myosin light chain. This insulin-induced phosphorylation is inhibited by calmodulin antagonists (e.g. TFP and W-7), suggesting that the phosphorylation is catalysed by MLCK. Together, these results strongly suggest that MLCK-mediated myosin light-chain phosphorylation plays an important role in regulating the membrane-associated actomyosin contraction required for the collection of insulin receptors into caps.

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26

Joshi, Satish, G. Thompson Burke, and Panayotis G. Katsoyannis. "Synthesis of an insulin-like compound consisting of the A chain of insulin and a B chain corresponding to the B domain of human insulin-like growth factor I." Biochemistry 24, no. 15 (July 1985): 4208–14. http://dx.doi.org/10.1021/bi00336a059.

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27

Berks, B. C., C. J. Marshall, A. Carne, S. M. Galloway, and J. F. Cutfield. "Isolation and structural characterization of insulin and glucagon from the holocephalan species Callorhynchus milii (elephantfish)." Biochemical Journal 263, no. 1 (October 1, 1989): 261–66. http://dx.doi.org/10.1042/bj2630261.

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Both insulin and glucagon from the pancreas of the holocephalan cartilaginous fish Callorhynchus milii (elephantfish) have been isolated and purified. Two reverse-phase h.p.l.c. steps enabled recovery of sufficient material for gas-phase sequencing of the intact chains as well as peptide digestion products. The elephantfish insulin sequence shows 14 differences from pig insulin, including two unusual substitutions, Val-A14 and Gln-B30, though none of these is thought likely to influence receptor binding significantly. The insulin B-chain contains 31 residues, one more than mammalian insulins, but markedly less than that of the closely related ratfish with which it otherwise exhibits high sequence similarity. Elephantfish and pig glucagons differ at only four positions, but there are six changes from the ratfish glucagon-36 (normal glucagon contains 29 residues) sequence. It is apparent that different prohormone proteolytic processing mechanisms operate in the two holocephalan species.

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28

Landreth, KS, R. Narayanan, and K. Dorshkind. "Insulin-like growth factor-I regulates pro-B cell differentiation." Blood 80, no. 5 (September 1, 1992): 1207–12. http://dx.doi.org/10.1182/blood.v80.5.1207.1207.

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Abstract Progression of B-lymphocyte development in the bone marrow of postnatal mammals is marked by progressive rearrangement and expression of immunoglobulin (Ig) heavy- and light-chain genes. Following productive VHDJH gene rearrangement in the Ig heavy-chain gene complex, mu-heavy chain is the first Ig gene product expressed in cells committed to the B-lymphoid differentiation pathway. Interleukin (IL)-7 has been shown to stimulate proliferation of pre-B cells following c mu expression and this proliferative stimulus is potentiated by kit ligand (KL). However, it appears that neither of these cytokines contributes to differentiation of pro-B cells or initiation of expression of Ig gene products. We previously demonstrated that differentiation of pro-B cells and expression of mu-heavy chain is stimulated by either bone marrow stromal cell line S17 or cell-free supernatants from that line. This biological activity was attributed to molecules with an apparent M(r) of less than 10 Kd and approximately 40 to 60 Kd. We now report that this biological activity resides with stromal cell-derived insulin- like growth factor-I (IGF-I). Recombinant IGF-I stimulated the expression of cytoplasmic mu-heavy chain in short-term bone marrow cultures and this stimulus was abrogated in the presence of anti-IGF-I antibody. We also demonstrate that either anti-IGF-I antibody or pretreatment of S17 cells with antisense oligonucleotide for IGF-I abrogated the pro-B cell differentiation activity of S17 stromal cell supernatants. Although IGF-I did not directly stimulate proliferation of B-lineage cells, like KL, it potentiated the proliferative stimulus provided by IL-7. Taken together, these data strongly suggest that IGF- I produced by bone marrow stromal cells in the hematopoietic microenvironment plays a key role in regulating primary B lymphopoiesis.

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Landreth, KS, R. Narayanan, and K. Dorshkind. "Insulin-like growth factor-I regulates pro-B cell differentiation." Blood 80, no. 5 (September 1, 1992): 1207–12. http://dx.doi.org/10.1182/blood.v80.5.1207.bloodjournal8051207.

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Progression of B-lymphocyte development in the bone marrow of postnatal mammals is marked by progressive rearrangement and expression of immunoglobulin (Ig) heavy- and light-chain genes. Following productive VHDJH gene rearrangement in the Ig heavy-chain gene complex, mu-heavy chain is the first Ig gene product expressed in cells committed to the B-lymphoid differentiation pathway. Interleukin (IL)-7 has been shown to stimulate proliferation of pre-B cells following c mu expression and this proliferative stimulus is potentiated by kit ligand (KL). However, it appears that neither of these cytokines contributes to differentiation of pro-B cells or initiation of expression of Ig gene products. We previously demonstrated that differentiation of pro-B cells and expression of mu-heavy chain is stimulated by either bone marrow stromal cell line S17 or cell-free supernatants from that line. This biological activity was attributed to molecules with an apparent M(r) of less than 10 Kd and approximately 40 to 60 Kd. We now report that this biological activity resides with stromal cell-derived insulin- like growth factor-I (IGF-I). Recombinant IGF-I stimulated the expression of cytoplasmic mu-heavy chain in short-term bone marrow cultures and this stimulus was abrogated in the presence of anti-IGF-I antibody. We also demonstrate that either anti-IGF-I antibody or pretreatment of S17 cells with antisense oligonucleotide for IGF-I abrogated the pro-B cell differentiation activity of S17 stromal cell supernatants. Although IGF-I did not directly stimulate proliferation of B-lineage cells, like KL, it potentiated the proliferative stimulus provided by IL-7. Taken together, these data strongly suggest that IGF- I produced by bone marrow stromal cells in the hematopoietic microenvironment plays a key role in regulating primary B lymphopoiesis.

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Muset, Graciela, Véronique Monnet, and Jean-Claude Gripon. "Intracellular proteinase ofLactococcus lactissubsp.lactisNCDO 763." Journal of Dairy Research 56, no. 5 (November 1989): 765–78. http://dx.doi.org/10.1017/s0022029900029344.

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SummaryAn intracellular proteinase was purified fromLactococcus lactissubsp.lactisNCDO 763 after spheroplast formation from cell wall proteinase-deficient variants. The proteinase was active at pH 7·5 and 45 °C and affected by metalloenzyme inhibitors. Its specificity, determined on B-chain of insulin, was thermolysin-like. The B-chain of insulin was hydrolysed rapidly while hydrolysis of β-casein was slower. This enzyme has aMrof ∽ 93000.

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Cepeda, Sarah S., and Kathryn B. Grant. "Hydrolysis of insulin chain B using zirconium(iv) at neutral pH." New Journal of Chemistry 32, no. 3 (2008): 388. http://dx.doi.org/10.1039/b715589a.

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Wang, Shu-hua, Shi-quan Hu, G. Thompson Burke, and Panayotis G. Katsoyannis. "Insulin analogues with modifications in the ?-turn of the B-chain." Journal of Protein Chemistry 10, no. 3 (June 1991): 313–24. http://dx.doi.org/10.1007/bf01025630.

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Dupradeau, François-Yves, Guillaume Le Flem, Jean-Michel Wieruszeski, Manuel Dauchez, Alain Alix, Véronique Larreta-Garde, and Jean-Pierre Monti. "Structural modifications of oxidized insulin B-chain induced by glycerol addition." Letters in Peptide Science 4, no. 4-6 (December 1997): 489–95. http://dx.doi.org/10.1007/bf02442922.

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Zhang, Bao-yan, Ming Liu, and Peter Arvan. "Behavior in the Eukaryotic Secretory Pathway of Insulin-containing Fusion Proteins and Single-chain Insulins Bearing Various B-chain Mutations." Journal of Biological Chemistry 278, no. 6 (November 21, 2002): 3687–93. http://dx.doi.org/10.1074/jbc.m209474200.

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35

Deberg, Michelle, Paule Houssa, Bruce H. Frank, Françoise Sodoyez-Goffaux, and Jean-Claude Sodoyez. "Highly specific radioimmunoassay for human insulin based on immune exclusion of all insulin precursors." Clinical Chemistry 44, no. 7 (July 1, 1998): 1504–13. http://dx.doi.org/10.1093/clinchem/44.7.1504.

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Abstract We describe a rapid and simple insulin RIA in which proinsulin and conversion intermediates do not interfere. Three monoclonal antibodies (S1, S2, and S53) were selected for their specificity (directed, respectively, against the B10 region, the junction between A chain and C-peptide, and the junction between B chain and C-peptide), their affinity constant (∼1010 L/mol), and their interactive properties in mixture. S2 and S53 were able to bind simultaneously to the same proinsulin molecule, whereas neither could bind simultaneously with S1. Preincubation of serum samples with an excess of S2 resulted in capture of proinsulin and conversion intermediates modified at the junction between B chain and C-peptide into immune complexes that no longer reacted with S1. Similarly, preincubation with S53 prevented proinsulin and conversion intermediates modified at the junction between A chain and C-peptide from reacting with S1. Preincubation with an excess of both S2 and S53 left insulin as the sole reactant with S1. Thus, separation of insulin precursors from insulin by mutually exclusive antibodies is feasible, and on the basis of this new principle, a highly specific RIA for insulin was designed. The detection limit was 11 pmol/L, and the inter- and intraassay coefficients of variation were 11% and 5%, respectively. The potential of the assay for use in clinical studies was verified by application to serum samples from control subjects and patients with diabetes or insulinoma.

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36

Smit, A. B., A. van Marle, R. van Elk, J. Bogerd, H. van Heerikhuizen, and W. P. M. Geraerts. "Evolutionary conservation of the insulin gene structure in invertebrates: cloning of the gene encoding molluscan insulin-related peptide III from Lymnaea stagnalis." Journal of Molecular Endocrinology 11, no. 1 (August 1993): 103–13. http://dx.doi.org/10.1677/jme.0.0110103.

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ABSTRACT Although insulins and structurally related peptides are found in vertebrates as well as in invertebrates, it is not clear whether the genes encoding these hormones have emerged from a single ancestral (insulin)-type of gene or, alternatively, have arisen independently through convergent evolution from different types of gene. To investigate this issue, we cloned the gene encoding the molluscan insulin-related peptide III (MIP III) from the freshwater snail, Lymnaea stagnalis. The predicted MIP III preprohormone had the overall organization of preproinsulin, with a signal peptide and A and B chains, connected by two putative C peptides. Although MIP III was found to share key features with vertebrate insulins, it also had unique structural characteristics in common with the previously identified MIPs I and II, thus forming a distinct class of MIP peptides within the insulin superfamily. MIP III is synthesized in neurones in the brain. It is encoded by a gene with the overall organization of the vertebrate insulin genes, with three exons and two introns, of which the second intron interrupts the coding region of the C peptides. Our data therefore demonstrate that in the Archaemetazoa, the common ancestor of the vertebrates and invertebrates, a primordial peptide with a two-chain insulin configuration encoded by a primordial insulin-type gene must have been present.

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Uchigata, Y., K. Yao, S. Takayama-Hasumi, and Y. Hirata. "Human Monoclonal IgG1 Insulin Autoantibody From Insulin Autoimmune Syndrome Directed at Determinant at Asparagine Site on Insulin B-Chain." Diabetes 38, no. 5 (May 1, 1989): 663–66. http://dx.doi.org/10.2337/diab.38.5.663.

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Uchigata, Y., K. Yao, S. Takayama-Hasumi, and Y. Hirata. "Human monoclonal IgG1 insulin autoantibody from insulin autoimmune syndrome directed at determinant at asparagine site on insulin B-chain." Diabetes 38, no. 5 (May 1, 1989): 663–66. http://dx.doi.org/10.2337/diabetes.38.5.663.

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39

Chen, Zhaohui, Michael P. Caulfield, Michael J. McPhaul, Richard E. Reitz, Steven W. Taylor, and Nigel J. Clarke. "Quantitative Insulin Analysis Using Liquid Chromatography–Tandem Mass Spectrometry in a High-Throughput Clinical Laboratory." Clinical Chemistry 59, no. 9 (September 1, 2013): 1349–56. http://dx.doi.org/10.1373/clinchem.2012.199794.

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BACKGROUND Circulating insulin concentrations reflect the amount of endogenous insulin produced by the pancreas and can be monitored to check for insulin resistance. Insulin is commonly measured using immunochemiluminometric assays (ICMA). Unfortunately, differing crossreactivities of the various ICMA antibodies have led to variability in assay results. In contrast, liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based approaches can provide a highly specific alternative to immunoassays. METHODS Insulin was extracted from patient serum and reduced to liberate the insulin B chain. Subsequent resolution of the peptide was achieved by LC coupled to triple-quadrupole MS. Selected-reaction monitoring of B-chain transitions was used for quantification. Recombinant human insulin was used as a calibrator and was compared against the National Institute for Biological Standards and Control (NIBSC) reference standard. Bovine insulin and a stable isotopic-labeled (13C/15N) human insulin B chain were used and compared as internal standards. RESULTS The LC-MS/MS assay described herein has been validated according to CLIA guidelines with a limit of detection of 1.8 μIU/mL (10.8 pmol/L) and a limit of quantitation of 3 μIU/mL (18.0 pmol/L). A correlation between the LC-MS/MS assay and a US Food and Drug Administration-approved ICMA was completed for patient samples and the resulting Deming regression revealed good agreement. A reference interval for the assay was established. CONCLUSIONS A simple, high-throughput, quantitative LC-MS/MS insulin assay traceable to the NIBSC standard has been successfully developed and validated.

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40

Song, H. Y., M. M. Abad, C. P. Mahoney, and R. C. McEvoy. "Human insulin B chain but not A chain decreases the rate of diabetes in BB rats." Diabetes Research and Clinical Practice 46, no. 2 (November 1999): 109–14. http://dx.doi.org/10.1016/s0168-8227(99)00080-7.

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41

Kaur, Zachary P., Alexander R. Ochman, John P. Mayer, Vasily M. Gelfanov, and Richard D. DiMarchi. "Discovery of High Potency, Single-Chain Insulin Analogs with a Shortened B-Chain and Nonpeptide Linker." ACS Chemical Biology 8, no. 8 (June 18, 2013): 1822–29. http://dx.doi.org/10.1021/cb4002624.

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42

Maimon, J., M. Mauro, K. C. Gorray, and B. S. Schneider. "Synthetic guinea pig insulin B-chain C-terminal decapeptide: a novel immunogen for generating immunocytochemical-grade antisera." Journal of Histochemistry & Cytochemistry 39, no. 11 (November 1991): 1571–74. http://dx.doi.org/10.1177/39.11.1918931.

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Antisera to guinea pig insulin are not commonly available, largely because of the short supply and limited immunogenicity of the intact hormone. To overcome these problems we have employed a novel reagent, synthetic guinea pig insulin B-chain C-terminal decapeptide, as a hapten for raising antibodies that react with intact guinea pig insulin. The decapeptide, coupled to bovine serum albumin, was successfully used as an immunogen in rabbits. The resulting anti-serum was employed for immunocytochemical staining of guinea pig insulin in pancreatic sections. The specificity of the staining was verified by both pre-absorption and pre-immune serum controls. The utility of this new antiserum for investigations of guinea pig insulin physiology is discussed.

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Dick, Lawrence R., Carolyn R. Moomaw, George N. DeMartino, and Clive A. Slaughter. "Degradation of oxidized insulin B chain by the multiproteinase complex macropain (proteasome)." Biochemistry 30, no. 10 (March 12, 1991): 2725–34. http://dx.doi.org/10.1021/bi00224a022.

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Wang, Chihchen, and Chenlu Tsou. "Interaction and reconstitution of carboxyl-terminal-shortened B chains with the intact A chain of insulin." Biochemistry 25, no. 18 (September 1986): 5336–40. http://dx.doi.org/10.1021/bi00366a052.

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45

Ramalingam, Tirunelveli S., Abhijit Chakrabarti, and Michael Edidin. "Interaction of Class I Human Leukocyte Antigen (HLA-I) Molecules with Insulin Receptors and Its Effect on the Insulin-Signaling Cascade." Molecular Biology of the Cell 8, no. 12 (December 1997): 2463–74. http://dx.doi.org/10.1091/mbc.8.12.2463.

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Insulin receptor (IR) and class I major histocompatibility complex molecules associate with one another in cell membranes, but the functional consequences of this association are not defined. We found that IR and human class I molecules (HLA-I) associate in liposome membranes and that the affinity of IR for insulin and its tyrosine kinase activity increase as the HLA:IR ratio increases over the range 1:1 to 20:1. The same relationship between HLA:IR and IR function was found in a series of B-LCL cell lines. The association of HLA-I and IR depends upon the presence of free HLA heavy chains. All of the effects noted were reduced or abrogated if liposomes or cells were incubated with excess HLA-I light chain, β2-microglobulin. Increasing HLA:IR also enhanced phosphorylation of insulin receptor substrate-1 and the activation of phosphoinositide 3-kinase. HLA-I molecules themselves were phosphorylated on tyrosine and associated with phosphoinositide 3-kinase when B-LCL were stimulated with insulin.

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Witsch, Esther J., Hong Cao, Hidehiro Fukuyama, and Martin Weigert. "Light chain editing generates polyreactive antibodies in chronic graft-versus-host reaction." Journal of Experimental Medicine 203, no. 7 (June 26, 2006): 1761–72. http://dx.doi.org/10.1084/jem.20060075.

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The chronic graft-versus-host (cGvH) reaction is a model of induced lupus caused by alloreactive CD4+ T cells from a Bm-12 mouse in a C57BL/6 recipient. We used this cGvH reaction in C57BL/6 anti-DNA H chain transgenic mice, 56R/B6, to understand the structure, specificity, and origin of the induced autoantibodies (auto-Abs). We found anti-DNA Abs that reacted to several different antigens, such as phosphatidylserine, myelin basic protein, thyroglobulin, histone, insulin, cytochrome C, and β-galactosidase. This polyreactivity was found for Abs from B cells that expressed the 56R H chain transgene with “editor” L chains that did not completely veto autoreactivity. We suggest that such incomplete editing results in polyreactivity and that incompletely edited polyreactive B cells influence the subsequent expression of pathogenic auto-Abs in disease. We also found B cells that coexpress κ and λ L chain. These B cells contributed to the autoimmune response and are possibly in the marginal zone of the spleen.

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Sheil, J. M., S. E. Shepherd, G. F. Klimo, and Y. Paterson. "Identification of an autologous insulin B chain peptide as a target antigen for H-2Kb-restricted cytotoxic T lymphocytes." Journal of Experimental Medicine 175, no. 2 (February 1, 1992): 545–52. http://dx.doi.org/10.1084/jem.175.2.545.

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We have examined the CD8+ peripheral T cell repertoire of C57BL/6 (H-2b) mice for cytotoxic T lymphocyte (CTL) reactivities to insulin, using in vitro immunization with a chymotryptic digest of reduced bovine insulin. The results presented in this study demonstrate that potentially autoreactive H-2Kb-restricted cytotoxic T cells specific for an autologous insulin B chain peptide are present in the preimmune splenic T cell repertoire. The immunogenic peptide comprises residues 7-15 from the insulin B chain and has features in common with naturally processed Kb-restricted peptides identified by others. The minimal peptide sequence recognized by these cytotoxic T cells is 10-15, which is highly conserved in mammalian species and constitutes a self-peptide in mice. The presence of class I major histocompatibility complex-restricted CTLs with potentially autoreactive specificities in preimmune animals raises the possibility of a role for such cells in autoimmune disease states. Possible mechanisms for the in vivo expansion of insulin peptide-specific CTLs are discussed.

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Ciszak, Ewa, John M. Beals, Bruce H. Frank, Jeffrey C. Baker, Nancy D. Carter, and G. David Smith. "Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric LysB28ProB29-human insulin." Structure 3, no. 6 (June 1995): 615–22. http://dx.doi.org/10.1016/s0969-2126(01)00195-2.

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Huang, Kun, Bin Xu, Shi-Quan Hu, Ying-Chi Chu, Qing-xin Hua, Yan Qu, Biaoru Li, et al. "How Insulin Binds: the B-Chain α-Helix Contacts the L1 β-Helix of the Insulin Receptor." Journal of Molecular Biology 341, no. 2 (August 2004): 529–50. http://dx.doi.org/10.1016/j.jmb.2004.05.023.

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Vilks, Karlis, Melita Videja, Marina Makrecka-Kuka, Martins Katkevics, Eduards Sevostjanovs, Aiga Grandane, Maija Dambrova, and Edgars Liepinsh. "Long-Chain Acylcarnitines Decrease the Phosphorylation of the Insulin Receptor at Tyr1151 Through a PTP1B-Dependent Mechanism." International Journal of Molecular Sciences 22, no. 12 (June 16, 2021): 6470. http://dx.doi.org/10.3390/ijms22126470.

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The accumulation of lipid intermediates may interfere with energy metabolism pathways and regulate cellular energy supplies. As increased levels of long-chain acylcarnitines have been linked to insulin resistance, we investigated the effects of long-chain acylcarnitines on key components of the insulin signalling pathway. We discovered that palmitoylcarnitine induces dephosphorylation of the insulin receptor (InsR) through increased activity of protein tyrosine phosphatase 1B (PTP1B). Palmitoylcarnitine suppresses protein kinase B (Akt) phosphorylation at Ser473, and this effect is not alleviated by the inhibition of PTP1B by the insulin sensitizer bis-(maltolato)-oxovanadium (IV). This result indicates that palmitoylcarnitine affects Akt activity independently of the InsR phosphorylation level. Inhibition of protein kinase C and protein phosphatase 2A does not affect the palmitoylcarnitine-mediated inhibition of Akt Ser473 phosphorylation. Additionally, palmitoylcarnitine markedly stimulates insulin release by suppressing Akt Ser473 phosphorylation in insulin-secreting RIN5F cells. In conclusion, long-chain acylcarnitines activate PTP1B and decrease InsR Tyr1151 phosphorylation and Akt Ser473 phosphorylation, thus limiting the cellular response to insulin stimulation.

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Journal articles on the topic 'Insulin chain-B'

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