Biology subjects

Reuveni, S.

Publications and source records attributed to Reuveni, S..

2 recordsLinked to original sources

bioRxiv2018

Multisite phosphorylation regulates phenotypic variability in antibiotic tolerance

Isogenic populations of cells exhibit phenotypic variability that has specific physiological consequences. For example, individual bacteria within a population can differ in their sensitivity to an antibiotic, but whether this variability can be regulated or is generally an unavoidable consequence of stochastic fluctuations is unclear. We observed that a bacterial stress response gene, the (p)ppGpp synthetase sasA, exhibits high levels of extrinsic noise in expression, suggestive of a regulatory process. We traced this variability to the convergence of two signaling systems that together control the multisite phosphorylation of a transcription factor, an event largely unexplored in bacteria, This regulatory intersection between a Ser/Thr kinase and a prototypical two component system is crucial for controlling the appearance of outliers, rare cells with unusually high levels of sasA expression. Additionally, by examining the full distributions of gene expression we calculated the contribution of the additional Ser/Thr kinase-dependent phosphorylation in setting the relative abundance of cells with a given a level of SasA. We then created a predictive model for the probability of a given cell surviving antibiotic treatment as a function of sasA expression. Therefore, our data show that multisite phosphorylation can be used to strongly regulate variations in phenotypes across a bacterial population.

microbiology↗

bioRxiv2016

Single-enzyme approach predicts natural emergence of inhibitor-activator duality

The classical theory of enzymatic inhibition aims to quantitatively describe the effect of certain molecules--called inhibitors--on the progression of enzymatic reactions, but growing signs indicate that it must be revised to keep pace with the single-molecule revolution that is sweeping through the sciences. Here, we take the single enzyme perspective and rebuild the theory of enzymatic inhibition from the bottom up. We find that accounting for multi-conformational enzyme structure and intrinsic randomness cannot undermine the validity of classical results in the case of competitive inhibition; but that it should strongly change our view on the uncompetitive and mixed modes of inhibition. There, stochastic fluctuations on the single-enzyme level could give rise to inhibitor-activator duality--a phenomenon in which, under some conditions, the introduction of a molecule whose binding shuts down enzymatic catalysis will counter intuitively work to facilitate product formation. We state--in terms of experimentally measurable quantities--a mathematical condition for the emergence of inhibitor-activator duality, and propose that it could explain why certain molecules that act as inhibitors when substrate concentrations are high elicit a non-monotonic dose response when substrate concentrations are low. The fundamental and practical implications of our findings are thoroughly discussed.

biophysics↗