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A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction

Author

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  • Franziska Zosel

    (University of Zurich
    Novo Nordisk A/S)

  • Davide Mercadante

    (University of Zurich)

  • Daniel Nettels

    (University of Zurich)

  • Benjamin Schuler

    (University of Zurich
    University of Zurich)

Abstract

The interactions of intrinsically disordered proteins (IDPs) with their molecular targets are essential for the regulation of many cellular processes. IDPs can perform their functions while disordered, and they may fold to structured conformations on binding. Here we show that the cis/trans isomerization of peptidyl−prolyl bonds can have a pronounced effect on the interactions of IDPs. By single-molecule spectroscopy, we identify a conserved proline residue in NCBD (the nuclear-coactivator binding domain of CBP) whose cis/trans isomerization in the unbound state modulates the association and dissociation rates with its binding partner, ACTR. As a result, NCBD switches on a time scale of tens of seconds between two populations that differ in their affinities to ACTR by about an order of magnitude. Molecular dynamics simulations indicate as a cause reduced packing of the complex for the cis isomer. Peptidyl-prolyl cis/trans isomerization may be an important previously unidentified mechanism for regulating IDP interactions.

Suggested Citation

  • Franziska Zosel & Davide Mercadante & Daniel Nettels & Benjamin Schuler, 2018. "A proline switch explains kinetic heterogeneity in a coupled folding and binding reaction," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05725-0
    DOI: 10.1038/s41467-018-05725-0
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    Cited by:

    1. Frederik Friis Theisen & Andreas Prestel & Steffie Elkjær & Yannick H. A. Leurs & Nicholas Morffy & Lucia C. Strader & Charlotte O’Shea & Kaare Teilum & Birthe B. Kragelund & Karen Skriver, 2024. "Molecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Markus Götz & Anders Barth & Søren S. -R. Bohr & Richard Börner & Jixin Chen & Thorben Cordes & Dorothy A. Erie & Christian Gebhardt & Mélodie C. A. S. Hadzic & George L. Hamilton & Nikos S. Hatzakis , 2024. "Reply to: On the statistical foundation of a recent single molecule FRET benchmark," Nature Communications, Nature, vol. 15(1), pages 1-4, December.

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