Multistite proteins have frequently been studied for their ability to produce all-or-none (ultrasensitive) responses to given stimuli. A widely made assumption is that of allostery, or the ability of one protein site to affect another through structural interactions. In recently published work by the PI and colleagues, it was shown that if more phosphorylation sites are present than are necessary for protein activation, a protein can produce ultrasensitive responses in the absence of allostery. In this project, the PI and graduate student will construct and analyze different input/output chemical reaction networks that are ultrasensitive (or bistable) as well as robust to stochastic noise and parameter changes. They will focus on nonsequential multisite networks in which ultrasensitivity or bistability arises naturally through network properties rather than through possibly restrictive conditions on parameter values (which are usually justified by allosteric properties). They will pursue specific applications beyond protein phosphorylation, such as DNA transcription regulation through packaging and histone modifications, signal transduction in clusters of membrane receptors, and gene expression regulation through binding of multiple identical transcription factors.
Cells are often faced with what one could describe as a decision to make: should it grow and divide in response to a given stimulus? Should it differentiate into a heart cell or a liver cell? Understanding the roots of cellular decision-making is a key problem in biology: for instance, a cell that divides too easily in response to a stimulus can - and often does - turn cancerous. In this proposal, the PI and student will seek to understand some of the basic mechanisms that cells likely use to produce such all-or-none behaviors. They will pursue an alternative to the so-called allosteric mechanism, which was first developed in work by Monod and others in 1965. While that elegant mechanism is rightly well known and widely cited, there may be many analogous biological systems where this property is not satisfied and which may have been overlooked. Recent work by the PI and colleagues provides an example of decision systems which are similar to allosteric systems but do not require that property. They will apply this principle to several specific systems of importance in molecular biology such as gene regulation and cell communication. They will also study the mathematical properties of these new systems and seek to collaborate with experimental biologists to determine to what extent these theoretical mechanisms represent actual biological functions.