Systems Model of T Cell Receptor Proximal Signaling Reveals Emergent Ultrasensitivity
Figure 5
Differential ZAP-70 affinity and sequential phosphorylation produces ultrasensitivity.
A) The concentration of bound ZAP-70 as a function of the relative concentration of active kinase (E) to phosphatase (F). Shown are the wild-type -chain (
123), and additional constructs where all ITAMs are identical (
222), switched (
321), or where phosphorylation is no longer sequential (
123 Random). The Hill numbers (inset) reveal that ultrasensitivity is decreased if ZAP-70 does not exhibit differential affinity (
222), if the affinity decreases as the
is sequentially phosphorylated (
321), or if phosphorylation is no longer sequential. B) Heat map of Hill numbers as a function of the ZAP-70 unbinding rate for ITAM 1 (Z
) and ITAM 3 (Z
), where the unbinding rate for ITAM 2 is fixed at 1 s−1. The calculation is performed under sequential phosphorylation. Maximum sensitivity is found in the top left of the heat map, where ZAP-70 binds with the largest affinity to ITAM 1 and with lowest affinity to ITAM 3. The heat map is repeated using an alternate measure of sensitivity in Fig. S3. Note that the heat map colour scheme in panel B is not related to the colour scheme in panel A.