A divergent INS protein in Caenorhabditis elegans structurally resembles human insulin and activates the human insulin receptor

  1. Qing-xin Hua1,
  2. Satoe H. Nakagawa2,
  3. Jill Wilken3,
  4. Rowena R. Ramos4,
  5. Wenhua Jia1,
  6. Joseph Bass4, and
  7. Michael A. Weiss1,5
  1. 1Department of Biochemistry, Case Western Reserve School of Medicine, Cleveland, Ohio 44106, USA; 2Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, USA; 3Gryphon Sciences, South San Francisco, California 94080, USA; 4Department of Medicine, Northwestern University Medical School and the ENH Research Institute, Evanston, Illionis 60208, USA

Abstract

Caenorhabditis elegans contains a family of putative insulin-like genes proposed to regulate dauer arrest and senescence. These sequences often lack characteristic sequence features of human insulin essential for its folding, structure, and function. Here, we describe the structure and receptor-binding properties of INS-6, a single-chain polypeptide expressed in specific neurons. Despite multiple nonconservative changes in sequence, INS-6 recapitulates an insulin-like fold. Although lacking classical receptor-binding determinants, INS-6 binds to and activates the human insulin receptor. Its activity is greater than that of an analogous single-chain human insulin analog.

Keywords

Footnotes

  • ↵5 Corresponding author.

  • E-MAIL weiss{at}biochemistry.cwru.edu; FAX (216) 368-3419.

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1058003.

    • Received November 12, 2002.
    • Accepted January 24, 2003.
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  1. Published in Advance March 21, 2003, doi: 10.1101/gad.1058003 Genes & Dev. 17: 826-831 Cold Spring Harbor Laboratory Press

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