A litmus test for classifying recognition mechanisms of transiently binding proteins

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 (), Thomas R. Weikl () and Christian Griesinger ()
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Kalyan S. Chakrabarti: Krea University
Simon Olsson: Chalmers University of Technology
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31374-5

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