A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction
Franziska Zosel1,2, Davide Mercadante1, Daniel Nettels1
1Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Nature Communications
|August 22, 2018
Summary
Cis/trans isomerization of peptidyl-prolyl bonds in intrinsically disordered proteins (IDPs) regulates interactions. A proline in NCBD switches between two states, altering binding affinity to ACTR by tenfold.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Intrinsically disordered proteins (IDPs) regulate cellular processes through interactions with molecular targets.
- IDPs can function while disordered or fold upon binding to targets.
Purpose of the Study:
- To investigate the role of cis/trans isomerization of peptidyl-prolyl bonds in regulating IDP interactions.
- To identify specific proline residues and their impact on protein binding dynamics.
Main Methods:
- Single-molecule spectroscopy was employed to study protein interactions.
- Molecular dynamics simulations were used to analyze structural changes and binding mechanisms.
Main Results:
- A conserved proline residue in NCBD (nuclear-coactivator binding domain of CBP) was identified.
- Cis/trans isomerization of this proline in the unbound state modulates association and dissociation rates with ACTR.
- NCBD switches between two populations with differing affinities (order of magnitude) on a timescale of tens of seconds.
- Molecular dynamics simulations suggest reduced packing in the complex for the cis isomer.
Conclusions:
- Peptidyl-prolyl cis/trans isomerization is a significant, previously unrecognized mechanism for regulating IDP interactions.
- This isomerization provides a dynamic regulatory switch for protein-protein binding.
- The findings offer new insights into the functional flexibility of IDPs.
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