Interaction Dynamics Determine Signaling and Output Pathway Responses

Stojanovski, Klement; Ferrar, Tony; Benisty, Hannah, 1986-; Uschner, Friedemann; Delgado Blanco, Javier; Jimenez, Javier; Solé, Carme; Nadal Clanchet, Eulàlia de; Klipp, E., 1965-; Posas Garriga, Francesc; Serrano Pubull, Luis, 1982-; Kiel, Christina

doi:http://dx.doi.org/10.1016/j.celrep.2017.03.029

Interaction Dynamics Determine Signaling and Output Pathway Responses

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Stojanovski K, Ferrar T, Benisty H, Uschner F, Delgado J, Jimenez J et al. Interaction Dynamics Determine Signaling and Output Pathway Responses. Cell Reports. 2017;19(1):136-49. DOI: 10.1016/j.celrep.2017.03.029

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 kon and koff displayed a lower threshold of HOG pathway activation than wild-type cells. Mutants with higher kon and koff rates gave rise to higher basal signaling and gene expression but impaired osmoadaptation. Thus, the kon and koff rates of the components in the Sln1 osmosensor determine proper signaling dynamics and osmoadaptation.