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Proline cis/trans Conformational Selection Controls 14-3-3 Binding.

Frederik F Theisen1,2, Andreas Prestel1, Nina L Jacobsen1

  • 1Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen DK-2200, Denmark.

Journal of the American Chemical Society
|February 5, 2025
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Summary
This summary is machine-generated.

Proline isomerization in intrinsically disordered protein regions (IDRs) creates distinct protein shapes. This study reveals proline isomer-specific binding to 14-3-3 proteins, impacting cellular signaling.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Dynamics

Background:

  • Intrinsically disordered protein regions (IDRs) are flexible and functional.
  • Short linear motifs (SLiMs) mediate protein interactions within IDRs.
  • Proline residues introduce slow cis/trans isomerization, affecting protein conformation.

Purpose of the Study:

  • Investigate the role of proline isomerization in the prolactin receptor (PRLR) and 14-3-3 protein interaction.
  • Determine the impact of proline cis/trans isomers on binding affinity and selectivity.
  • Understand the structural basis for proline isomer-dependent binding.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Thermodynamic profiling
  • Molecular Dynamics (MD) simulations

Main Results:

  • A significant difference in binding affinity was observed between proline cis and trans isomers.
  • The cis conformation exhibited an affinity three orders of magnitude higher than the trans conformation.
  • MD simulations revealed structural constraints in the 14-3-3 binding groove explaining isomer selectivity.
  • The cis preference of PRLR impacts signal propagation kinetics and protein chain direction.

Conclusions:

  • Proline isomerization is a critical factor in the specificity of IDR-mediated interactions.
  • This isomer-dependent binding mechanism is relevant to the 14-3-3 interactome.
  • Considering proline isomer properties is essential for understanding IDR function and designing experiments.