The Limited Information Capacity of Cross-Reactive Sensors Drives the Evolutionary Expansion of Signaling

Abstract

Graphical Abstract Highlights d Cooperativity or allostery do not increase the signaling capacity d Copy number variation and cross-reactivity severely restrict signaling capacity d Duplication of cross-reactive receptors doubles capacity even with minimal divergence d Duplication with minimal divergence yields multiple crosswired signaling pathways SUMMARYSignaling systems expand by duplications of various components, be it receptors or downstream effectors. However, whether and how duplicated components contribute to higher signaling capacity is unclear, especially because in most cases, their specificities overlap. Using information theory, we found that augmentation of capacity by an increase in the copy number is strongly limited by logarithmic diminishing returns. Moreover, counter to conventional biochemical wisdom, refinements of the response mechanism, e.g., by cooperativity or allostery, do not increase the overall signaling capacity. However, signaling capacity nearly doubles when a promiscuous, non-cognate ligand becomes explicitly recognized via duplication and partial divergence of signaling components. Our findings suggest that expansion of signaling components via duplication and enlistment of promiscuously acting cues is virtually the only accessible evolutionary strategy to achieve overall high-signaling capacity despite overlapping specificities and molecular noise. This mode of expansion also explains the highly cross-wired architecture of signaling pathways. mone-receptor complexity by molecular exploitation. Science 312, 97-101.

Information-theoretic analysis of multivariate single-cell signaling responses

“…The output, Y , is an activity of one or more signaling effectors, e.g., of transcription factors quantified over time. As cellular signaling systems are inherently stochastic, the information about the input contained in the output is imprecise and only a limited number of input values can be resolved [6, 15, 20, 21]. To date, a number of studies have experimentally examined fidelity of various signaling systems, e.g., [13, 15, 19, 22–24].…”

Modeling cell-specific dynamics and regulation of the common gamma chain cytokines

“…Receptor families with many receptors and ligands are often made up of a dense web of connections, making the role of individual components non-intuitive (Antebi et al, 2017b;Eubelen et al, 2018). Interconnected, cross-reactive components may have evolved as a tradeoff between transmitting ligand-mediated information and expanding the repertoire of cell-surface proteins (Komorowski and Tawfik, 2019). The methods detailed in this paper can be applied to many signaling systems characterized by pleiotropy and high dimensionality.…”

Information propagation in time through allosteric signaling

“…This naive picture is immediately complicated by allostery, a process of remote regulation of functional activity by which biological macro-molecules, such as proteins, transmit the effect of ligand binding from one site to a distal functional site [4,[10][11][12][13][14]. Several studies have been performed using information theory to analyze the role of allosteric regulation in signaling pathways [15,16]. These studies primarily explored the thermodynamics of substrate binding through allostery.…”