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Disordered Regions Flanking the Binding Interface Modulate Affinity between CBP and NCOA.

Elin Karlsson1, Jan Schnatwinkel2, Cristina Paissoni3

  • 1Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, SE-75123 Uppsala, Sweden.

Journal of Molecular Biology
|May 23, 2022
PubMed
Summary
This summary is machine-generated.

Flanking intrinsically disordered regions enhance protein binding affinity through non-specific hydrophobic contacts, not electrostatics. This fuzzy binding mechanism regulates interactions, offering insights into intrinsically disordered protein regions.

Keywords:
affinitybinding motifflanking regionsintrinsically disordered proteinsprotein interactions

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Protein-protein interactions often involve recognition motifs within intrinsically disordered regions (IDRs).
  • The flanking regions of these motifs in IDRs are less understood regarding their role in binding.
  • The interaction between NCOA3 (ACTR) and CBP involves coupled binding and folding of their CID and NCBD domains.

Purpose of the Study:

  • To quantify the contribution of flanking regions of NCOA3's CID domain to its interaction with CBP's NCBD.
  • To elucidate the biophysical mechanism by which these flanking regions modulate binding affinity.
  • To explore the role of intrinsically disordered protein regions in regulating protein-protein interactions.

Main Methods:

  • Circular dichroism spectroscopy to assess structural changes.
  • Kinetic measurements to determine binding rates and affinities.
  • Site-directed mutagenesis and molecular dynamics simulations to probe interactions.
  • Experiments at varying ionic strengths to investigate electrostatic contributions.

Main Results:

  • Flanking regions of CID promote binding to NCBD in an additive manner.
  • These regions remain largely disordered even within the protein complex.
  • Binding enhancement is not due to electrostatic interactions but short-lived, non-specific hydrophobic contacts.
  • The interaction exhibits characteristics of 'fuzzy binding' with highly frustrated interactions.

Conclusions:

  • Flanking regions of intrinsically disordered protein regions can significantly modulate binding affinity through non-canonical interactions.
  • This fuzzy binding mechanism, driven by transient hydrophobic contacts, represents a novel mode of interaction regulation.
  • Modulation of affinity by flanking IDRs may be a general mechanism for regulating protein function.