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IGF-dependent dynamic modulation of a protease cleavage site in the intrinsically disordered linker domain of human IGFBP2
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  • Garima Jaipuria,
  • Divya Shet,
  • Shahid Malik,
  • Monalisa Swain,
  • Hanudatta S. Atreya,
  • Charles A. Galea,
  • Mark G. Slomiany,
  • Steven A. Rosenzweig,
  • Briony E. Forbes,
  • Raymond Norton,
  • Somnath Mondal
Garima Jaipuria
Indian Institute of Science
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Divya Shet
Indian Institute of Science
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Shahid Malik
Indian Institute of Science
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Monalisa Swain
Indian Institute of Science
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Hanudatta S. Atreya
Indian Institute of Science
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Charles A. Galea
Monash Institute of Pharmaceutical Sciences
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Mark G. Slomiany
Medical University of South Carolina
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Steven A. Rosenzweig
Medical University of South Carolina
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Briony E. Forbes
Flinders University
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Raymond Norton
Monash Institute of Pharmaceutical Sciences
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Somnath Mondal
Indian Institute of Science
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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.

Peer review status:UNDER REVIEW

12 Nov 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
16 Nov 2021Assigned to Editor
16 Nov 2021Submission Checks Completed
24 Nov 2021Reviewer(s) Assigned