Positive feedback induces switch between distributive and processive phosphorylation of Hog1

Maximilian Mosbacher, Sung Sik Lee, Gilad Yaakov, Mariona Nadal-Ribelles, Eulàlia Nadal, Frank Drogen, Francesc Posas, Matthias Peter () and Manfred Claassen ()
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Maximilian Mosbacher: Institute of Biochemistry, ETH Zurich
Sung Sik Lee: Institute of Biochemistry, ETH Zurich
Gilad Yaakov: Universitat Pompeu Fabra (UPF)
Mariona Nadal-Ribelles: Universitat Pompeu Fabra (UPF)
Eulàlia Nadal: Universitat Pompeu Fabra (UPF)
Frank Drogen: Institute of Biochemistry, ETH Zurich
Francesc Posas: Universitat Pompeu Fabra (UPF)
Matthias Peter: Institute of Biochemistry, ETH Zurich
Manfred Claassen: Institute of Molecular Systems Biology, ETH Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Cellular decision making often builds on ultrasensitive MAPK pathways. The phosphorylation mechanism of MAP kinase has so far been described as either distributive or processive, with distributive mechanisms generating ultrasensitivity in theoretical analyses. However, the in vivo mechanism of MAP kinase phosphorylation and its activation dynamics remain unclear. Here, we characterize the regulation of the MAP kinase Hog1 in Saccharomyces cerevisiae via topologically different ODE models, parameterized on multimodal activation data. Interestingly, our best fitting model switches between distributive and processive phosphorylation behavior regulated via a positive feedback loop composed of an affinity and a catalytic component targeting the MAP kinase-kinase Pbs2. Indeed, we show that Hog1 directly phosphorylates Pbs2 on serine 248 (S248), that cells expressing a non-phosphorylatable (S248A) or phosphomimetic (S248E) mutant show behavior that is consistent with simulations of disrupted or constitutively active affinity feedback and that Pbs2-S248E shows significantly increased affinity to Hog1 in vitro. Simulations further suggest that this mixed Hog1 activation mechanism is required for full sensitivity to stimuli and to ensure robustness to different perturbations.

Date: 2023
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DOI: 10.1038/s41467-023-37430-y

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