Figure 4

Skeleton Model 2. FIH-release is determined by the FIH sequestration capacity of the ARD protein pool, and by the efficiency of AR-hydroxylation. The sequestration capacity κ depends on the total concentration of ARs and on their affinity for FIH. The hydroxylation efficiency β relates the maximal rate of AR hydroxylation to the average turnover rate of ARD proteins. Free FIH (blue curves) and unhydroxylated, FIH sequestering ankyrin repeats (grey curves) are plotted either against ${\overline{O}}_2$, the oxygen concentration relative to the K_M of FIH for oxygen (A and B) or against time expressed in units of the mean life time of an average ARD protein (C and D). A. Signal/response curves. Varyingκstrongly affects the dynamic range of free FIH. If κ is larger, FIH is sequestered more efficiently in the absence of oxygen. FIH-release is sharper and the dynamic range of free FIH is increased. Note that varying κ does not significantly affect the oxygen-threshold of FIH-release from AR-dependent sequestration. B. Signal/response curves. β sets the oxygen-threshold for FIH-release. Varying β strongly affects the oxygen-tension at which FIH-release occurs, however does not affect the slope of the signal/response curves. C and D. Time-resolved response to reoxygenation after hypoxia. The system was equilibrated at ${\overline{O}}_2$ = 0.01 (hypoxia, light grey area). At t = 0, oxygen was increased to ${\overline{O}}_2$ = 0.5 (reoxygenation) and the system response was simulated. C. Varying κ changes the sharpness, but not the timing of the response. Increasing κ sharpens the time-dependence of FIH-release. Note the time delay until half-maximal response (about 0.5 time units), which is insensitive to variations in κ. D. Varying β changes both the sharpness and the timing of the response. The larger β, the more rapid and more pronounced is the FIH-release.