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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

Corresponding Author:[email protected]

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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.
12 Nov 2021Submitted to PROTEINS: Structure, Function, and Bioinformatics
16 Nov 2021Submission Checks Completed
16 Nov 2021Assigned to Editor
24 Nov 2021Reviewer(s) Assigned
22 Jan 2022Review(s) Completed, Editorial Evaluation Pending
31 Jan 2022Editorial Decision: Revise Minor
03 Mar 20221st Revision Received
04 Mar 2022Submission Checks Completed
04 Mar 2022Assigned to Editor
07 Mar 2022Reviewer(s) Assigned
10 Mar 2022Review(s) Completed, Editorial Evaluation Pending
22 Mar 2022Editorial Decision: Accept
Sep 2022Published in Proteins: Structure, Function, and Bioinformatics volume 90 issue 9 on pages 1732-1743. 10.1002/prot.26350