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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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1437-4315
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Volume 386, Issue 11 (Nov 2005)

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Proinsulin lacking the A7-B7 disulfide bond, Ins2Akita, tends to aggregate due to the exposed hydrophobic surface

Takeo Yoshinaga
  • Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
/ Keisuke Nakatome
  • Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
/ Jun-ichi Nozaki
  • Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
/ Motoko Naitoh
  • Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan
/ Jun Hoseki
  • Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan and Core Research for Evolutional Science/Japan Science Technology Agency (CREST/JST), Kawaguchi, Saitama 332-0012, Japan
/ Hiroshi Kubota
  • Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan and Core Research for Evolutional Science/Japan Science Technology Agency (CREST/JST), Kawaguchi, Saitama 332-0012, Japan
/ Kazuhiro Nagata
  • Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan and Core Research for Evolutional Science/Japan Science Technology Agency (CREST/JST), Kawaguchi, Saitama 332-0012, Japan
/ Akio Koizumi
  • Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
Published Online: 2005-11-24 | DOI: https://doi.org/10.1515/BC.2005.124

Abstract

A single mutation (C96Y) in the Ins2 gene, which disrupts the A7-B7 disulfide bond, causes the diabetic phenotype in Akita mice. We biochemically analyzed the conformation of wild-type and Akita mutant recombinant proinsulins. Gel filtration chromatography and dynamic light scattering revealed that the apparent size of the mutant proinsulin molecules was significantly larger than that of wild-type proinsulin, even in the absence of intermolecular disulfide bonds. Titration with a hydrophobic probe, 1-anilinonaphthalene-8-sulfonate, demonstrated that the mutant proinsulin was more hydrophobic than the wild type. In addition, circular dichroism studies revealed that the conformation of the mutant proinsulin was less stable than the wild type, which is consistent with the observation that hydrophobic residues are exposed on the surface of the proinsulin molecules. Studies with antiserum against the C-peptide of proinsulin indicated that the mutant proinsulin had an immunoreactivity that was at least one-tenth weaker than wild-type proinsulin, suggesting that the C-peptide of mutant proinsulin is buried inside the aggregate of the proinsulin molecule. These findings indicate that increased hydrophobicity of mutant proinsulin facilitates aggregate formation, providing a clue to the dominant negative effect in the Akita mouse.

Keywords: aggregation; β-cell dysfunction; C96Y mutation of diabetes; disulfide bond; hydrophobic surface; Ins2Akita

References

About the article

Corresponding author


Received: February 21, 2005

Accepted: August 11, 2005

Published Online: 2005-11-24

Published in Print: 2005-11-01



Citation Information: Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2005.124. Export Citation

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