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
Summary
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.
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.
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