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

Garima Jaipuria, Divya Shet, Shahid Malik, Monalisa Swain, Hanudatta S. Atreya, Charles A. Galea, Mark G. Slomiany, Steven A. Rosenzweig, Briony E. Forbes, Raymond S. Norton, Somnath Mondal

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Number of pages12
JournalProteins: Structure, Function and Bioinformatics
Early online date20 Apr 2022
DOIs
Publication statusE-pub ahead of print - 20 Apr 2022
Externally publishedYes

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

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