Daniel D. Seaton and J. Krishnan
systems biology, physiological modeling, biological systems modeling, synergistic activation of pathways
The phosphatidylinositol signalling pathway is responsible for regulating a wide variety of processes in the cell via its regulation of intracellular calcium levels. This pathway is known to respond synergistically to certain combinations of signals. Key components in this pathway are the isoforms of PLCß, which are capable of binding two upstream effectors, Gαq and Gßγ, and may do this in an allosteric way. We present a modelling investigation into how two different isoforms of PLCß, PLCß2 and PLCß3, displaying different degrees of allostery, may interact with one another to modify the overall pathway synergy. We show how the synergy depends on both the absolute and relative concentrations of the two isoforms, and explain these effects mechanistically through the uptake of Gαq and Gßγ by PLCß2 and PLCß3. From a systems perspective, this illustrates how synergy, which is present at a single-molecule level through allostery, is modified in the context of a pathway. Furthermore, it allows consideration of how this effect may be significant in the wider system, which consists of many other downstream interconnections and feedbacks.
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