Positive feedback induces switch between distributive and processive phosphorylation of Hog1

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• dc.contributor.author Mosbacher, Maximilian
• dc.contributor.author Lee, Sung Sik
• dc.contributor.author Yaakov, Gilad
• dc.contributor.author Nadal Ribelles, Mariona, 1984-
• dc.contributor.author Nadal Clanchet, Eulàlia de
• dc.contributor.author van Drogen, Frank
• dc.contributor.author Posas Garriga, Francesc
• dc.contributor.author Peter, Matthias
• dc.contributor.author Claassen, Manfred
• dc.date.accessioned 2023-06-14T13:47:24Z
• dc.date.available 2023-06-14T13:47:24Z
• dc.date.issued 2023
• dc.description.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.
• dc.description.sponsorship We are grateful to A. Smith for critical reading of the manuscript and members of the Claassen- and Peter laboratories for helpful discussions. Research in the Peter lab was funded by the Swiss National Science Foundation, the European Research Council (ERC), ETH Zurich and the Global Research Laboratory (NRF-2015K1A1A2033054) through the National Research Foundation of Korea (NRF). Research in the Claassen lab was supported by internal funds of ETH Zurich. The study was supported by grants from the Spanish Ministry of Economy and Competitiveness (PGC2018-094136-B-I00 to F.P.; BFU2017-85152-P and FEDER to E.dN.), the Catalan Government (2017 SGR 799). We gratefully acknowledge institutional funding from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Catalan Government and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M). M.N.-R. is a recipient of a Maria de Maeztu Postdoctoral Fellowship (Doctores Banco de Santander-María de Maeztu at Universitat Pompeu Fabra), and F.P. received an ICREA Acadèmia award (Generalitat de Catalunya). We acknowledge support from the Open Access Publication Fund of the University of Tübingen.
• dc.format.mimetype application/pdf
• dc.identifier.citation Mosbacher M, Lee SS, Yaakov G, Nadal-Ribelles M, de Nadal E, van Drogen F, Posas F, Peter M, Claassen M. Positive feedback induces switch between distributive and processive phosphorylation of Hog1. Nat Commun. 2023 Apr 29;14(1):2477. DOI: 10.1038/s41467-023-37430-y
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-023-37430-y
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/57163
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2023 Apr 29;14(1):2477
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-094136-B-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-85152-P
• dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Computer modelling
• dc.subject.keyword Differential equations
• dc.subject.keyword Dynamic networks
• dc.subject.keyword Robustness
• dc.title Positive feedback induces switch between distributive and processive phosphorylation of Hog1
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion