Allostery Beyond Amplification: Temporal Regulation of Signaling Information

TL;DR

Allostery is reinterpreted as a regulator of temporal information flow in signaling networks, not merely a modulator of steady-state activity. The authors develop a stochastic, chemical master equation–based framework to quantify the mutual information $MI_{AB}$ between an allosterically regulated upstream enzyme $A$ and a downstream component $B$, and to study how substrate dynamics shape the timing and duration of coupling. They show that $MI_{AB}$ is maximized at an intermediate substrate flux $\beta$, with the optimal point shifting according to the K-type and V-type allosteric parameters $\xi_K$ and $\xi_V$, and that temporal inputs can induce informative spikes in coupling independent of mean product levels. This work demonstrates that temporal information processing can be tuned via allosteric regulation, enabling conserved signaling architectures to support diverse physiological timescales and differentiation without altering pathway topology.

Abstract

Allostery is a fundamental mechanism of protein regulation and is commonly interpreted as modulating enzymatic activity or product abundance. Here we show that this view is incomplete. Using a stochastic model of allosteric regulation combined with an information-theoretic analysis, we quantify the mutual information between an enzyme's regulatory state and the states of downstream signaling components. Beyond controlling steady-state production levels, allostery also regulates the timing and duration over which information is transmitted. By tuning the temporal operating regime of signaling pathways, allosteric regulation enables distinct dynamical outcomes from identical molecular components, providing a physical mechanism for temporal information flow, signaling specificity, and coordination without changes in metabolic pathways.

Figures (4)

• Figure 1: Diagram of the allosteric reaction network. The substrate $S$ is produced at rate $\beta$ and degraded at rate $\gamma_S$, and interacts with the upstream (sender) enzyme $A$. Enzyme $A$ occupies four internal states: unbound baseline ($A$), unbound allosterically modified ($A^\ast$), substrate-bound baseline ($AS$), and substrate-bound allosterically modified ($A^\ast S$). The state $A^\ast$ represents an allosterically modified conformation stabilized by binding of an allosteric ligand (shown in brown). Allosteric switching between $A$ and $A^\ast$ modulates both substrate affinity and catalytic turnover. K-type allostery is quantified by the ratio $\xi_K = k_{A^\ast \mathrm{on}}/k_{A\mathrm{on}}$, which captures changes in substrate association rates, while V-type allostery is quantified by the ratio $\xi_V = \nu^\ast/\nu$, which captures changes in product generation rates. The product $P$ is either degraded at rate $\gamma_P$ or sequestered by the downstream (receiver) enzyme $B$, which transitions between the unbound state $B$ and the product-bound state $BP$.
• Figure 2: Calibrating the V- and K-type allosteric ratios allows for fine-tuning of the communication between the enzyme $A$ and the downstream protein $B$. The steady-state mutual information $\mathrm{MI}_{AB}$ as a function of the normalized substrate production rate $\beta/\gamma_S$ is shown for different combinations of K-type ($\xi_K$) and V-type ($\xi_V$) allostery. For all allosteric regimes, information transmission is maximized at an intermediate substrate flux, reflecting a balance between insufficient coupling at low flux and downstream saturation at high flux. The substrate flux that maximizes $\mathrm{MI}_{AB}$ (vertical dashed lines) depends sensitively on the allosteric parameters, demonstrating that K- and V-type allostery shift both the magnitude of transmitted information and the system’s optimal operating point.
• Figure 3: Allostery is not simply about making more product. Steady-state metrics across a range of relative production rates, $\beta/\gamma_S$. The metrics shown, from top to bottom, are the mutual information between the states of $A$ and $B$ ($\text{MI}_{AB}$), the expected amount of substrate $\langle S \rangle$, and the expected amount of product $\langle P \rangle$ in the environment, all calculated at steady state. For a silent K-type allosteric, $\xi_K=1$, across all values of $\beta/\gamma_S$, we observe that mutual information increases at both low (negative cooperativity) and high (positive cooperativity) V-type allosteric ratio, $\xi_V$. This increase in mutual information at high V-type allosteric ratio can be attributed to the rapid production rate, where $A$ and $B$ become sequentially active, and this is reflected in the variations of $\langle S \rangle$ and $\langle P \rangle$. Conversely, the increase in mutual information at low allosteric (in both cases) rates indicates that even when allostery represents inhibition and, therefore, there is low production of $P$, communication between $A$ and $B$ is stronger.
• Figure 4: Allostery regulates coupling between enzyme, $A$, and the downstream protein, $B$, in response to external variation in the substrate concentration, thereby providing a time order for downstream signaling. Time traces of key metrics with varying substrate relative production rates, $\beta/\gamma_S$, change in time in cycles as shown in the top panel. On the left-hand side, we fix K-allostery to be silent ($\xi_K = 1$) and vary V-allostery: blue denotes negative V-allostery ($\xi_V = 0.1$), orange denotes silent V-allostery ($\xi_V = 1$), and green denotes positive V-allostery ($\xi_V = 10$). On the right-hand side, we show the symmetric case, where V-allostery is silent ($\xi_V = 1$) and K-allostery is varied analogously. The mutual information between the states of $A$ and $B$ spikes shortly after the increase in $\beta/\gamma$, even when $\langle P \rangle$ shows no significant changes. Interestingly, and consistent with the results in Fig. \ref{['fig:main_steady']}, the increase in mutual information is more pronounced at lower allosteric rates.