(284c) A General Model for Ultrasensitivity Arising from Single Protein Multisite Modifications

Many biological systems show switch-like responses to external signals. Such behavior is characterized by the sigmoidal stimulus-response curve, which generates little response to low stimulus (i.e. noise filtering), changes abruptly from minimum to maximum responses over a small range of stimulus beyond a certain threshold, and compresses changes at high stimulus level. This property, also termed ultrasensitivity, has been observed widely at various levels ranging from single molecules to pathways and is crucial for the regulation of numerous biological processes, such as cell cycle progression and cell fate decision.

Multisite phosphorylation has been conjectured as a source of ultrasensitive responses. However, the underlying mechanism by which ultrasensitivity arises in such systems has largely remained unclear. We have proposed in this work a mathematical model which reveals the design principle for achieving ultrasensitivity through multisite phosphorylations. The basic features of the model include: i) a chain of different phosphorylation states of the substrate protein caused by not-fully-processive kinase/phosphatase; and ii) increasing activities of the different phosphorylation states along the chain. We have further quantitatively characterized how the degree of ultrasensitivity is determined by various properties of a multisite system. The proposed model is capable of explaining mechanistically the switch-like behavior of many biological systems, including the degradation of Sic1 protein during the G1/S transition in yeast cells. In light of its generality and simplicity, as well as the widespread occurrence of multisite proteins, the revealed mechanism may constitute a major paradigm for achieving biological switching. Quantitative experiments are in progress to test directly the validity of the proposed model.