Gpa1 synthesis/degradation

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• Gpa1^N388K mutants, which don't bind Ste4:Ste18, are degraded 3-7 fold faster than WT Gpa1. Schauber et al. 1998 PMID 9685182
  • It was shown that Gpa1(N388K) is a poorly expressed dominant negative suppressor of signalling (which can bind Ste4:Ste18), and thus isn't a good model for Gpa1 stability. Wu et al. 2004 PMID 15197187

• Gpa1 is degraded via the N-end rule pathway, and has a half-life of ~50 min. Madura and Varshavsky 1994 PMID 8073290

• Gpa1 is mono-ubiquitinated and degraded by the vacuole, and poly-ubiquitinated and degraded by the proteasome. Wang et al. 2005 PMID 15519996
  • The distribution of Gpa1 between mono- and poly-ubiquitination is unaffected by pheromone exposure and deletion of Ste2.

Reaction Definition

Gpa1 half-life has been measured to be ~50 min, so kdeg_Gpa1 = ln(2) / (50 min) = 2.3 * 10^-4 s^-1.

Synthesis of Gpa1 must balance the degradation of Gpa1, to give the steady state amount of Gpa1 in the absence of pheromone (Gpa1_tot_conc). Since the degradation rate and concentration of Gpa1 are measured independently, and then the synthesis rate inferred, we use measured internalization rates and Gpa1 abundances to calculate the synthesis rate. Thus ksynth_Gpa1 = Gpa1_tot_conc * kdeg_Gpa1.

For pheromone-induced synthesis of Gpa1, please see Ste12 mediated protein synthesis. When Ste12 mediated protein synthesis is included in a model, the synthesis of Gpa1 through the reaction specified here together with synthesis of Gpa1 through basal pathway activation of Ste12 (in the absence of pheromone) should balance the degradation rate. So when Ste12 mediated protein synthesis is included in a model, ksynth_Gpa1 should be decreased by the amount of Gpa1 synthesis that occurs through basal activation of Ste12. This cannot be determined a priori because the basal activation of Ste12 in unknown.

Gpa1 + Cell -> Cell

• Degradation rate constant kdeg_Gpa1

• In order for the degradation reaction to selectively degrade Gpa1 out of a complex, we need to include the parameter DeleteMolecules

• Dummy species Cell used because BioNetGen requires at least one species on each side of reaction

Cell -> Cell + Gpa1(Ste2_site, Ste4_site, nucleotide~GTP)

• Synthesis rate constant ksynth_Gpa1

• Dummy species Cell used because BioNetGen requires at least one species on each side of reaction