1. Molecular Sciences Institute, 2168 Shattuck Avenue, Berkeley, California 94704, USA
2. Microscale Life Sciences Center, University of Washington, Seattle, Washington 98195, USA
3. Present addresses: Instituto de Fisiología, Biología Molecular y Neurociencias, CONICET and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina (A.C.-L.); Synopsys, Mountain View, California 94043, USA (L.L.); Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158, USA (D.P.); Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona 08907, Spain (E.S.); Biodesign Institute, Arizona State University, Tempe, Arizona 85387, USA (M.H.); Amyris Biotechnologies, Emeryville, California 94608, USA (K.B.); Physics Department, Brookhaven National Laboratory, Upton, New York 11973, USA (A.G.).

Correspondence to: Richard C. Yu¹Roger Brent¹ Correspondence and requests for materials should be addressed to Email: ryu@molsci.org and Email: brent@molsci.org.

Abstract

Haploid Saccharomyces cerevisiae yeast cells use a prototypic cell signalling system to transmit information about the extracellular concentration of mating pheromone secreted by potential mating partners. The ability of cells to respond distinguishably to different pheromone concentrations depends on how much information about pheromone concentration the system can transmit. Here we show that the mitogen-activated protein kinase Fus3 mediates fast-acting negative feedback that adjusts the dose response of the downstream system response to match the dose response of receptor-ligand binding. This 'dose–response alignment', defined by a linear relationship between receptor occupancy and downstream response, can improve the fidelity of information transmission by making downstream responses corresponding to different receptor occupancies more distinguishable and reducing amplification of stochastic noise during signal transmission. We also show that one target of the feedback is a previously uncharacterized signal-promoting function of the regulator of G-protein signalling protein Sst2. Our work suggests that negative feedback is a general mechanism used in signalling systems to align dose responses and thereby increase the fidelity of information transmission.

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