Hsu, I. S. | bioRxiv Science

bioRxiv2018

An analog to digital converter creates nuclear localization pulses in yeast calcium signaling

Several examples of transcription factors that show stochastic, unsynchronized pulses of nuclear localization have been described. Here we show that under constant calcium stress, nuclear localization pulses of the transcription factor Crz1 follow stochastic variations in cytoplasmic calcium concentration. We find that the size of the stochastic calcium pulses is positively correlated with the number of subsequent Crz1 pulses. Based on our observations, we propose a simple stochastic model of how the signaling pathway converts a constant external calcium concentration into a digital number of Crz1 pulses in the nucleus, due to the time delay from nuclear transport and the stochastic decoherence of individual Crz1 molecule dynamics. We find support for several additional predictions of the model and conclude that stochastic input to nuclear transport may produce digital responses to analog signals in other signaling systems.

systems biology↗

bioRxiv2017

Short linear motifs in intrinsically disordered regions modulate HOG signaling capacity

The effort to characterize intrinsically disordered regions of signaling proteins is rapidly expanding. An important class of disordered interaction modules are ubiquitous and functionally diverse elements known as short linear motifs (SLiMs). To further examine the role of SLiMs in signal transduction, we used a previously devised bioinformatics method to predict evolutionarily conserved SLiMs within a well-characterized pathway in S. cerevisiae. Using a single cell, reporter-based flow cytometry assay in conjunction with a fluorescent reporter driven by a pathway-specific promoter, we quantitatively assessed pathway output via systematic deletions of individual motifs. We found that, when deleted, 34% (10/29) of predicted SLiMs displayed a significant decrease in pathway output, providing evidence that these motifs play a role in signal transduction. In addition, we show that perturbations of parameters in a previously published stochastic model of HOG signaling could reproduce the quantitative effects of 4 out of 7 mutations in previously unknown SLiMs. Our study suggests that, even in well-characterized pathways, large numbers of functional elements remain undiscovered, and that challenges remain for application of systems biology models to interpret the effects of mutations in signalling pathways.\n\nOne-sentence SummaryMutations of short conserved elements in disordered regions have quantitative effects on a model signaling pathway.

systems biology↗