Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity

Bianca J. Van Lierop, Shee Chee Ong, Alessia Belgi, Carlie A. Delaine, Sofianos Andrikopoulos, Naomi L. Haworth, John G.T. Menting, Michael Colin Lawrence, Andrea Jane Robinson, Briony E. Forbes

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    Abstract

    The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin's ability to engage its receptor. We reveal that in native insulin, contraction of the Cα-Cα distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is also permitted in the cis isomer, with its shorter Cα-Cα distance, but prevented in the extended trans analogue. These findings thus illuminate for the first time the allosteric role of the A6-A11 bond in mediating the transition of the hormone to an active conformation, significantly advancing our understanding of insulin action and opening up new avenues for the design of improved therapeutic analogues.

    Original languageEnglish
    Article number17239
    Number of pages14
    JournalScientific Reports
    Volume7
    DOIs
    Publication statusPublished - 1 Dec 2017

    Bibliographical note

    Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

    Keywords

    • insulin
    • Glucose homeostasis
    • ring-closing metathesis
    • A6-A11 disulfide
    • stereo-isomers

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  • Cite this

    Van Lierop, B. J., Ong, S. C., Belgi, A., Delaine, C. A., Andrikopoulos, S., Haworth, N. L., Menting, J. G. T., Lawrence, M. C., Robinson, A. J., & Forbes, B. E. (2017). Insulin in motion: The A6-A11 disulfide bond allosterically modulates structural transitions required for insulin activity. Scientific Reports, 7, [17239]. https://doi.org/10.1038/s41598-017-16876-3