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SUMMARY:A “scaffold” protein mediates accuracy\, fidelity and robustne
 ss of a cell fate decision - Prof. Stephen Michnick\, Department of Bioche
 mistry\, University of Montreal
DTSTART:20110524T150000Z
DTEND:20110524T160000Z
UID:TALK31524@talks.cam.ac.uk
CONTACT:M. Madan Babu
DESCRIPTION:Evolution has resulted in numerous innovations that allow orga
 nisms to maximize their fitness by choosing particular mating partners\, i
 ncluding secondary sexual characteristics\, behavioural patterns\, chemica
 l attractants and corresponding sensory mechanisms. The haploid yeast Sacc
 haromyces cerevisiae selects mating partners by interpreting the spatial c
 oncentration gradient of pheromone secreted by potential mates through a n
 etwork of mitogen-activated protein kinase (MAPK) signaling proteins. The 
 mating decision in yeast is an all-or-none\, or switch-like\, response tha
 t allows cells to make accurate decisions about which among alternative po
 tential partners to mate with by responding only at or above critical conc
 entrations when a mate is sufficiently close. The molecular mechanisms tha
 t govern the switch-like mating decision are poorly understood.  \n\nWe ha
 ve demonstrated that the switching mechanism arises from competition betwe
 en 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 t
 hat resembles “zero-order ultrasensitivity”\, which is robust to varia
 tions in the concentrations of these proteins\, thus buffering genetic var
 iation between individuals.  We further demonstrate that an early event\, 
 the recruitment of Ste5 to plasma membrane\, is ultrasensitive and that ul
 trasensitivity is generated by dephosphorylation of eight N-terminal phosp
 hosites on Ste5 by the phosphatase Ptc1. Polarized assembly of protein com
 plexes at the plasma membrane surface is a general theme recapitulated in 
 all organisms from bacteria to humans. Such complexes can increase the eff
 iciency\, fidelity and specificity of signal transduction. \n\nThus\, our 
 results demonstrate that accuracy\, fidelity and robustness of the pheromo
 ne response occurs through regulation of the stoichiometry of phosphorylat
 ion 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 efficien
 cy of information processing. Regulation of dynamic signal-response charac
 teristics through such modular regulation of clusters of phosphosites on s
 caffold proteins may be a general means by which polarized cell fate decis
 ions are achieved. Similar mechanisms may govern cellular decisions in hig
 her organisms and be disrupted in pathological states.\n\nThe scaffold pro
 tein Ste5 directly controls a switch-like mating decision in yeast.\nMalle
 shaiah MK\, Shahrezaei V\, Swain PS\, Michnick SW.\nNature. 2010 May 6\;46
 5(7294):101-5. 
LOCATION:Max Perutz Lecture Theatre\, MRC Laboratory of Molecular Biology\
 , Cambridge\, UK
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