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A litmus test for classifying recognition mechanisms of transiently binding proteins

Author

Listed:
  • Kalyan S. Chakrabarti

    (Krea University
    Max Planck Institute for Multidisciplinary Sciences)

  • Simon Olsson

    (Chalmers University of Technology
    Freie Universität Berlin)

  • Supriya Pratihar

    (Max Planck Institute for Multidisciplinary Sciences)

  • Karin Giller

    (Max Planck Institute for Multidisciplinary Sciences)

  • Kerstin Overkamp

    (Max Planck Institute for Multidisciplinary Sciences)

  • Ko On Lee

    (Korea Basic Science Institute, Korea Basic Science Institute, Ochang-Eup)

  • Vytautas Gapsys

    (Max Planck Institute for Multidisciplinary Sciences)

  • Kyoung-Seok Ryu

    (Korea Basic Science Institute, Korea Basic Science Institute, Ochang-Eup)

  • Bert L. Groot

    (Max Planck Institute for Multidisciplinary Sciences)

  • Frank Noé

    (Freie Universität Berlin
    Freie Universität Berlin
    Rice University)

  • Stefan Becker

    (Max Planck Institute for Multidisciplinary Sciences)

  • Donghan Lee

    (University of Louisville)

  • Thomas R. Weikl

    (Max Planck Institute of Colloids and Interfaces)

  • Christian Griesinger

    (Max Planck Institute for Multidisciplinary Sciences)

Abstract

Partner recognition in protein binding is critical for all biological functions, and yet, delineating its mechanism is challenging, especially when recognition happens within microseconds. We present a theoretical and experimental framework based on straight-forward nuclear magnetic resonance relaxation dispersion measurements to investigate protein binding mechanisms on sub-millisecond timescales, which are beyond the reach of standard rapid-mixing experiments. This framework predicts that conformational selection prevails on ubiquitin’s paradigmatic interaction with an SH3 (Src-homology 3) domain. By contrast, the SH3 domain recognizes ubiquitin in a two-state binding process. Subsequent molecular dynamics simulations and Markov state modeling reveal that the ubiquitin conformation selected for binding exhibits a characteristically extended C-terminus. Our framework is robust and expandable for implementation in other binding scenarios with the potential to show that conformational selection might be the design principle of the hubs in protein interaction networks.

Suggested Citation

  • Kalyan S. Chakrabarti & Simon Olsson & Supriya Pratihar & Karin Giller & Kerstin Overkamp & Ko On Lee & Vytautas Gapsys & Kyoung-Seok Ryu & Bert L. Groot & Frank Noé & Stefan Becker & Donghan Lee & Th, 2022. "A litmus test for classifying recognition mechanisms of transiently binding proteins," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31374-5
    DOI: 10.1038/s41467-022-31374-5
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    References listed on IDEAS

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