The role of stochastic sequestration dynamics for intrinsic noise filtering in signaling network motifs

Abstract

The relation between design principles of signaling network motifs and their robustness against intrinsic noise still remains illusive. In this work we investigate the role of cascading for coping with intrinsic noise due to stochasticity in molecular reactions. We use stochastic approaches to quantify fluctuations in the terminal kinase of phosphorylation-dephosphorylation cascade motifs and demonstrate that cascading highly affects these fluctuations. We show that this purely stochastic effect can be explained by time-varying sequestration of upstream kinase molecules. In particular, we discuss conditions on time scales and parameter regimes which lead to a reduction of output fluctuations. Our results are put into biological context by adapting rate parameters of our modeling approach to biologically feasible ranges for general binding-unbinding and phosphorylation-dephosphorylation mechanisms. Overall, this study reveals a novel role of stochastic sequestration for dynamic noise filtering in signaling cascade motifs.

Stochastic Sequestration Promotes Specificity in Decision Making in Single Cells

“…Single cells often need to discriminate between signals represented by differences in ligand concentrations, ligand affinities, or the durations of transient ligand concentrations. , However, such specific cell responses in many instances involve nonspecific molecular interactions. − One illustrative example is the regulation of gene expressions by the large noncoding region in the DNA or the so-called “junk” DNA. The noncoding region in the DNA contains many “decoy” sites that can nonspecifically bind to proteins or transcription factors. , In budding yeast, the decoy sites sequester transcription factors and generate a switch-like response to a graded signal input. , Several theoretical models ,− have been developed over the years to investigate the mechanistic roles of decoy sites in generating specific features of gene regulation such as the independence of the steady-state number of transcription factors from the number of decoy sites or the suppression of noise in downstream reactions. However, most of these investigations have been carried out in the steady states or with stationary input signals.…”