Polyelectrolyte interactions enable rapid association and dissociation in high-affinity disordered protein complexes

Andrea Sottini, Alessandro Borgia, Madeleine B. Borgia, Katrine Bugge, Daniel Nettels, Aritra Chowdhury, Pétur O. Heidarsson, Franziska Zosel, Robert B. Best (), Birthe B. Kragelund () and Benjamin Schuler ()
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Andrea Sottini: University of Zurich
Alessandro Borgia: University of Zurich
Madeleine B. Borgia: University of Zurich
Katrine Bugge: Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, Ole Maaloes Vej 5, University of Copenhagen
Daniel Nettels: University of Zurich
Aritra Chowdhury: University of Zurich
Pétur O. Heidarsson: University of Zurich
Franziska Zosel: University of Zurich
Robert B. Best: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Birthe B. Kragelund: Structural Biology and NMR Laboratory (SBiNLab) and REPIN, Department of Biology, Ole Maaloes Vej 5, University of Copenhagen
Benjamin Schuler: University of Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Highly charged intrinsically disordered proteins can form complexes with very high affinity in which both binding partners fully retain their disorder and dynamics, exemplified by the positively charged linker histone H1.0 and its chaperone, the negatively charged prothymosin α. Their interaction exhibits another surprising feature: The association/dissociation kinetics switch from slow two-state-like exchange at low protein concentrations to fast exchange at higher, physiologically relevant concentrations. Here we show that this change in mechanism can be explained by the formation of transient ternary complexes favored at high protein concentrations that accelerate the exchange between bound and unbound populations by orders of magnitude. Molecular simulations show how the extreme disorder in such polyelectrolyte complexes facilitates (i) diffusion-limited binding, (ii) transient ternary complex formation, and (iii) fast exchange of monomers by competitive substitution, which together enable rapid kinetics. Biological polyelectrolytes thus have the potential to keep regulatory networks highly responsive even for interactions with extremely high affinities.

Date: 2020
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DOI: 10.1038/s41467-020-18859-x

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