Positive feedback induces switch between distributive and processive phosphorylation of Hog1

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 k...

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Autores: Mosbacher, Maximilian, Lee, Sung Sik, Yaakov, Gilad, Nadal Ribelles, Mariona, Nadal Clanchet, Eulàlia De, van Drogen, Frank, Posas, Francesc, Peter, Matthias, Claassen, Manfred
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/201923
Acceso en línea:https://hdl.handle.net/2445/201923
Access Level:acceso abierto
Palabra clave:Proteïnes quinases
Fosforilació
Saccharomyces cerevisiae
Protein kinases
Phosphorylation
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spelling Positive feedback induces switch between distributive and processive phosphorylation of Hog1Mosbacher, MaximilianLee, Sung SikYaakov, GiladNadal Ribelles, MarionaNadal Clanchet, Eulàlia Devan Drogen, FrankPosas, FrancescPeter, MatthiasClaassen, ManfredProteïnes quinasesFosforilacióSaccharomyces cerevisiaeProtein kinasesPhosphorylationSaccharomyces cerevisiaeCellular 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.Springer Nature Limited2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/201923Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41467-023-37430-yNature Communications, 2023, vol. 14, num. 1, p. 2477https://doi.org/10.1038/s41467-023-37430-ycc by (c) Mosbacher, Maximilian et al., 2023http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2019232026-05-27T06:46:51Z
dc.title.none.fl_str_mv Positive feedback induces switch between distributive and processive phosphorylation of Hog1
title Positive feedback induces switch between distributive and processive phosphorylation of Hog1
spellingShingle Positive feedback induces switch between distributive and processive phosphorylation of Hog1
Mosbacher, Maximilian
Proteïnes quinases
Fosforilació
Saccharomyces cerevisiae
Protein kinases
Phosphorylation
Saccharomyces cerevisiae
title_short Positive feedback induces switch between distributive and processive phosphorylation of Hog1
title_full Positive feedback induces switch between distributive and processive phosphorylation of Hog1
title_fullStr Positive feedback induces switch between distributive and processive phosphorylation of Hog1
title_full_unstemmed Positive feedback induces switch between distributive and processive phosphorylation of Hog1
title_sort Positive feedback induces switch between distributive and processive phosphorylation of Hog1
dc.creator.none.fl_str_mv Mosbacher, Maximilian
Lee, Sung Sik
Yaakov, Gilad
Nadal Ribelles, Mariona
Nadal Clanchet, Eulàlia De
van Drogen, Frank
Posas, Francesc
Peter, Matthias
Claassen, Manfred
author Mosbacher, Maximilian
author_facet Mosbacher, Maximilian
Lee, Sung Sik
Yaakov, Gilad
Nadal Ribelles, Mariona
Nadal Clanchet, Eulàlia De
van Drogen, Frank
Posas, Francesc
Peter, Matthias
Claassen, Manfred
author_role author
author2 Lee, Sung Sik
Yaakov, Gilad
Nadal Ribelles, Mariona
Nadal Clanchet, Eulàlia De
van Drogen, Frank
Posas, Francesc
Peter, Matthias
Claassen, Manfred
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes quinases
Fosforilació
Saccharomyces cerevisiae
Protein kinases
Phosphorylation
Saccharomyces cerevisiae
topic Proteïnes quinases
Fosforilació
Saccharomyces cerevisiae
Protein kinases
Phosphorylation
Saccharomyces cerevisiae
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/201923
url https://hdl.handle.net/2445/201923
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-023-37430-y
Nature Communications, 2023, vol. 14, num. 1, p. 2477
https://doi.org/10.1038/s41467-023-37430-y
dc.rights.none.fl_str_mv cc by (c) Mosbacher, Maximilian et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Mosbacher, Maximilian et al., 2023
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature Limited
publisher.none.fl_str_mv Springer Nature Limited
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300724

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