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A “scaffold” protein mediates accuracy, fidelity and robustness of a cell fate decision

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Evolution has resulted in numerous innovations that allow organisms to maximize their fitness by choosing particular mating partners, including secondary sexual characteristics, behavioural patterns, chemical attractants and corresponding sensory mechanisms. The haploid yeast Saccharomyces cerevisiae selects mating partners by interpreting the spatial concentration gradient of pheromone secreted by potential mates through a network of mitogen-activated protein kinase (MAPK) signaling proteins. The mating decision in yeast is an all-or-none, or switch-like, response that allows cells to make accurate decisions about which among alternative potential partners to mate with by responding only at or above critical concentrations when a mate is sufficiently close. The molecular mechanisms that govern the switch-like mating decision are poorly understood.

We have demonstrated that the switching mechanism arises from competition between the MAPK Fus3 and a phosphatase Ptc1 for control of the phosphorylation state of four sites on the scaffold protein Ste5. The architecture of the Fus3–Ste5–Ptc1 circuit generates a novel ultrasensitivity mechanism that resembles “zero-order ultrasensitivity”, which is robust to variations in the concentrations of these proteins, thus buffering genetic variation between individuals. We further demonstrate that an early event, the recruitment of Ste5 to plasma membrane, is ultrasensitive and that ultrasensitivity is generated by dephosphorylation of eight N-terminal phosphosites on Ste5 by the phosphatase Ptc1. Polarized assembly of protein complexes at the plasma membrane surface is a general theme recapitulated in all organisms from bacteria to humans. Such complexes can increase the efficiency, fidelity and specificity of signal transduction.

Thus, our results demonstrate that accuracy, fidelity and robustness of the pheromone response occurs through regulation of the stoichiometry of phosphorylation of two clusters of phosphosites on Ste5 by Ptc1 and Fus3. The role of Ste5 as a direct modulator of a cell-fate decision expands the functional repertoire of scaffold proteins beyond providing specificity and efficiency of information processing. Regulation of dynamic signal-response characteristics through such modular regulation of clusters of phosphosites on scaffold proteins may be a general means by which polarized cell fate decisions are achieved. Similar mechanisms may govern cellular decisions in higher organisms and be disrupted in pathological states.

The scaffold protein Ste5 directly controls a switch-like mating decision in yeast. Malleshaiah MK, Shahrezaei V, Swain PS, Michnick SW. Nature. 2010 May 6;465(7294):101-5.

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