The genetic architecture of protein interaction affinity and specificity

Alexandra M. Bendel, Andre J. Faure, Dominique Klein, Kenji Shimada, Romane Lyautey, Nicole Schiffelholz, Georg Kempf, Simone Cavadini, Ben Lehner () and Guillaume Diss ()
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Alexandra M. Bendel: Friedrich Miescher Institute for Biomedical Research (FMI)
Andre J. Faure: The Barcelona Institute of Science and Technology
Dominique Klein: Friedrich Miescher Institute for Biomedical Research (FMI)
Kenji Shimada: Friedrich Miescher Institute for Biomedical Research (FMI)
Romane Lyautey: Friedrich Miescher Institute for Biomedical Research (FMI)
Nicole Schiffelholz: Friedrich Miescher Institute for Biomedical Research (FMI)
Georg Kempf: Friedrich Miescher Institute for Biomedical Research (FMI)
Simone Cavadini: Friedrich Miescher Institute for Biomedical Research (FMI)
Ben Lehner: The Barcelona Institute of Science and Technology
Guillaume Diss: Friedrich Miescher Institute for Biomedical Research (FMI)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract The encoding and evolution of specificity and affinity in protein-protein interactions is poorly understood. Here, we address this question by quantifying how all mutations in one protein, JUN, alter binding to all other members of a protein family, the 54 human basic leucine zipper transcription factors. We fit a global thermodynamic model to the data to reveal that most affinity changing mutations equally affect JUN’s affinity to all its interaction partners. Mutations that alter binding specificity are relatively rare but distributed throughout the interaction interface. Specificity is determined both by features that promote on-target interactions and by those that prevent off-target interactions. Approximately half of the specificity-defining residues in JUN contribute both to promoting on-target binding and preventing off-target binding. Nearly all specificity-altering mutations in the interaction interface are pleiotropic, also altering affinity to all partners. In contrast, mutations outside the interface can tune global affinity without affecting specificity. Our results reveal the distributed encoding of specificity and affinity in an interaction interface and how coiled-coils provide an elegant solution to the challenge of optimizing both specificity and affinity in a large protein family.

Date: 2024
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DOI: 10.1038/s41467-024-53195-4

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