Abstract
Multisite phosphorylation (and generally multisite modification) is a basic way of encoding substrate function and circuits/networks of post-translational modifications (PTM) are ubiquitous in cell signalling. The information processing characteristics of PTM systems are a focal point of broad interest. The ordering of modifications is a key aspect of multisite modification, and a broad synthesis of the impact of ordering of modifications is still missing. We focus on a basic class of multisite modification circuits: the cyclic mechanism, which corresponds to the same ordering of phosphorylation and dephosphorylation, and examine multiple variants involving common/separate kinases and common/separate phosphatases. This is of interest both because it is encountered in concrete cellular contexts, and because it serves as a bridge between ordered (sequential) mechanisms (representing one type of ordering) and random mechanisms (which have no ordering). We show that bistability and biphasic dose response curves of the maximally modified phosphoform are ruled out for basic structural reasons independent of parameters, while oscillations can result with even just one shared enzyme. We then examine the effect of relaxing some basic assumptions about the ordering of modification. We show computationally and analytically how bistability, biphasic responses and oscillations can be generated by minimal augmentations to the cyclic mechanism even when these augmentations involved reactions operating in the unsaturated limit. All in all, using this approach we demonstrate (1) how the cyclic mechanism (with single augmentations) represents a modification circuit using minimal ingredients (in terms of shared enzymes and sequestration of enzymes) to generate bistability and oscillations, when compared to other mechanisms, (2) new design principles for rationally designing PTM systems for a variety of behaviour, (3) a basis and a necessary step for understanding the origins and robustness of behaviour observed in basic multisite modification systems.
Highlights
Ordering of modifications is a fundamental aspect of multisite modification and in present in a range of contexts and guises
Cyclic mechanisms are of interest because (1) they represent a particular ordering and a model system for enzymatic multisite modification, and a basic post-translation modification network and can be a reference for engineering synthetic multisite modification (2) they are found in natural systems (3) they are, from a network perspective, a bridge between ordered sequential and random mechanisms (4) analysis of this system provides and consolidates insights into the origins of different types of information processing characteristics observed in ordered and random distributive mechanisms
With the presence of a single reversible reaction, we identify multiple categories of responses: (1) those where biphasic responses are ruled out for the kinase enzyme(s): in the case where there are two kinase enzymes, they are ruled out for both
Summary
(4) Absence of biphasic dose response curves for specific models (C11) of the cyclic mechanism with common kinase and phosphatase, with one augmentation. (5) Absence of biphasic dose response curve for models (C22, C31, C32) of the cyclic mechanism with separate kinase and phosphatase, as the total amount of enzyme K1 is varied.
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