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IGF‐dependent dynamic modulation of a protease cleavage site in the intrinsically disordered linker domain of human IGFBP2

Jaipuria, Garima and Shet, Divya and Malik, Shahid and Swain, Monalisa and Atreya, Hanudatta S. and Galea, Charles A. and Slomiany, Mark G. and Rosenzweig, Steven A. and Forbes, Briony E. and Norton, Raymond S. and Mondal, Somnath (2022) IGF‐dependent dynamic modulation of a protease cleavage site in the intrinsically disordered linker domain of human IGFBP2. In: Proteins: Structure, Function, and Bioinformatics . ISSN 0887-3585

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Official URL: https://doi.org/10.1002/prot.26350


Functional regulation via conformational dynamics is well known in structured proteins but less well characterized in intrinsically disordered proteins and their complexes. Using NMR spectroscopy, we have identified a dynamic regulatory mechanism in the human insulin-like growth factor (IGF) system involving the central, intrinsically disordered linker domain of human IGF-binding protein-2 (hIGFBP2). The bioavailability of IGFs is regulated by the proteolysis of IGF-binding proteins. In the case of hIGFBP2, the linker domain (L-hIGFBP2) retains its intrinsic disorder upon binding IGF-1, but its dynamics are significantly altered, both in the IGF binding region and distantly located protease cleavage sites. The increase in flexibility of the linker domain upon IGF-1 binding may explain the IGF-dependent modulation of proteolysis of IGFBP2 in this domain. As IGF homeostasis is important for cell growth and function, and its dysregulation is a key contributor to several cancers, our findings open up new avenues for the design of IGFBP analogs inhibiting IGF-dependent tumors.

Item Type: Journal Article
Publication: Proteins: Structure, Function, and Bioinformatics
Additional Information: The copyright of this article belongs to the author.
Keywords: conformational dynamics of intrinsically disordered protein; disordered protein; function–dynamics relationship of disordered protein; human IGF-binding protein-2; human insulin-like growth factor system; intrinsically disordered protein; NMR; protein-NMR; protein–protein interaction; proteolysis
Department/Centre: Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility)
Date Deposited: 23 May 2022 10:21
Last Modified: 23 May 2022 10:21
URI: https://eprints.iisc.ac.in/id/eprint/72418

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