Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)

Abstract

BackgroundRap proteins from Bacilli directly target response regulators of bacterial two-component systems and modulate their activity. Their effects are controlled by binding of signaling peptides to an allosteric site. Hence Raps exemplify a class of monomeric signaling receptors, which we call switchable allosteric modulator proteins (SAMPs). These proteins have potential applications in diverse biomedical and biotechnical settings, but a quantitative understanding of the impact of molecular and cellular factors on signal transduction is lacking. Here we introduce mathematical models that elucidate how signals are propagated though the network upon receptor stimulation and control the level of active response regulator.ResultsBased on a systematic parameter analysis of the models, we show that key features of the dose-response behavior at steady state are controlled either by the molecular properties of the modulator or the signaling context. In particular, we find that the biochemical activity (i.e. non-enzymatic vs. enzymatic) and allosteric properties of the modulator control the response amplitude. The Hill coefficient and the EC50 are controlled in addition by the relative ligand affinities. By tuning receptor properties, either graded or more switch-like (memory-less) response functions can be fashioned. Furthermore, we show that other contextual factors (e.g. relative concentrations of network components and kinase activity) have a substantial impact on the response, and we predict that there exists a modulator concentration which is optimal for response amplitude.ConclusionWe discuss data on Rap-Phr systems in B. subtilis to show how our models can contribute to an integrated view of SAMP signaling by combining biochemical, structural and physiological insights. Our results also suggest that SAMPs could be evolved or engineered to implement diverse response behaviors. However—without additional regulatory controls—they can generate rather variable cellular outputs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0274-3) contains supplementary material, which is available to authorized users.

Effects of stevia on synaptic plasticity and NADPH oxidase level of CNS in conditions of metabolic disorders caused by fructose

“…We can assume that under impaired glucose metabolism conditions stevia adapts neuronal brain network by stablishment of depression/or strengthening of depression mediated by activation of excitatory neurotransmitters. Data on the short-term activation and long-term depressor effects were in favor in the functioning of Stevia as an allosteric modulator, which is consistent with the concept of molecular and cellular factors controlling signal transduction via transferred allosteric modulator proteins, a key one being G-protein-coupled receptor for natural substrates [ 60 ]. At the systemic level, allosteric modulation of Stevia provides for neuroprotection by long-term changes of allosteric ligands, which in turn leads to an increase in neurotrophic factors.This intriguing possibility requires further investigation.…”

Ratiometric population sensing by a pump-probe signaling system in Bacillus subtilis

“…After signals are pumped into the cell, the intracellular signal concentration is probed by RRNPP-type receptors. Raps belongs to a subclass of RRNPP receptors termed switchable allosteric modulator proteins (SAMPs) 46 , because they modulate the activity of response regulators; Phr peptides switch this interaction by binding to the receptor in a 1:1 stoichiometry at an allosteric site 4,40 , and structural studies suggest competitive allosteric inhibition as the dominant mode of signal transduction 4,40 . While the analysis of receptor function in vitro is very advanced, functional in vivo analyses have lagged behind.…”

“…In support of this inference, the in vitro action of PhrA on RapA is best described by a partial noncompetitive inhibition mechanism 25 , which implies that PhrA-RapA-Spo0F complexes contribute to signaling. Thus upon activation, Raps may remain (partially) bound to their (unphosphorylated) response-regulator targets 24 , which could fine-tune the cellular response to receptor stimulation 46 . Since our experiments were conducted under nonsporulating conditions, FRET likely reports on the interaction of RapA with unphosphorylated Spo0F.…”

Analysis of network motifs in cellular regulation: Structural similarities, input–output relations and signal integration

“…The same pattern was also used in a pharmacological context to estimate the binding affinities of drugs that interact allosterically with a receptor (Ehlert, 1988). Recently, this motif has been studied in the context of twocomponent signaling where a signaling molecule controls the interaction between a modulator and a response regulator (Babel and Bischofs, 2016). The steady states of the cooperative-binding motif are described by 3 of the 4 binding equilibria, e.g.…”