title: Interaction Dynamics Determine Signaling and Output Pathway Responses.
abstract: The understanding of interaction dynamics in signaling pathways can shed light on pathway architecture and provide insights into targets for intervention. Here, we explored the relevance of kinetic rate constants of a key upstream osmosensor in the yeast high-osmolarity glycerol-mitogen-activated protein kinase (HOG-MAPK) pathway to signaling output responses. We created mutant pairs of the Sln1-Ypd1 complex interface that caused major compensating changes in the association (kon) and dissociation (koff) rate constants (kinetic perturbations) but only moderate changes in the overall complex affinity (Kd). Yeast cells carrying a Sln1-Ypd1 mutant pair with moderate increases in konand koffdisplayed a lower threshold of HOG pathway activation than wild-type cells. Mutants with higher konand koffrates gave rise to higher basal signaling and gene expression but impaired osmoadaptation. Thus, the konand koffrates of the components in the Sln1 osmosensor determine proper signaling dynamics and osmoadaptation.
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Klement
authors.initials: K
authors.lastname: Stojanovski
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Tony
authors.initials: T
authors.lastname: Ferrar
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Hannah
authors.initials: H
authors.lastname: Benisty
authors.affiliation: Theoretical Biophysics, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Uschner
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Delgado
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Jimenez
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Solé
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Eulalia
authors.initials: E
authors.lastname: de Nadal
authors.affiliation: Theoretical Biophysics, Humboldt-Universität zu Berlin, 10115 Berlin, Germany.
authors.forename: Edda
authors.initials: E
authors.lastname: Klipp
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. Electronic address: francesc.posas@upf.edu.
authors.forename: Francesc
authors.initials: F
authors.lastname: Posas
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, 08003 Barcelona, Spain; ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain. Electronic address: luis.serrano@crg.eu.
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, 08003 Barcelona, Spain. Electronic address: christina.kiel@crg.eu.
authors.forename: Christina
authors.initials: C
authors.lastname: Kiel
mesh_terms: D048429:Cell Size; D005786:Gene Expression Regulation; D005990:Glycerol / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009994:Osmolar Concentration; D009997:Osmotic Pressure; D010766:Phosphorylation; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C102035:YPD1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; C083749:SLN1 protein, S cerevisiae; D005990:Glycerol
keywords: HOG-MAPK pathway; kinetic perturbations; osmostress response; phosphorelay