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Nutrient sensing, metabolism and cellular decision making

One of the main determinants of the cell fitness is its ability to integrate multiple yeast_cellscues about nutrient availability from the environment and coordinate its metabolism and regulatory networks accordingly. Impaired nutrient sensing results in growth defects and plays a role in the pathogenesis of diseases such as cancer and diabetes. A classical example for the ability of cells to sense multiple signals and execute a regulatory program in response is that of catabolite repression and diauxic growth.

We study how s. cerevisiae responds to an environment that contains a mixture of preferred carbon source, glucose, and less preferred one, galactose. We have found that instead of simply inhibiting galactose utilization when glucose is above a threshold concentration, individual cells respond to the ratio of glucose and galactose and based on this ratio determine whether to induce genes involved in galactose metabolism. We also investigate, theoretically and experimentally, the fitness impact of ratio sensing.

Our work suggests that a critical portion of information processing in a major metabolic decision is made upstream of the canonical signaling network and highlights the dual role transporters can play in both nutrient uptake and signal integration.

Savir, Y., Tu, BP, Springer, M. (2015) Competitive Inhibition Can Linearize Dose-Response and Generate a Linear Rectifier. Cell Systems
(see also Preview and Editorial)

Escalante R.*, Savir, Y.*, Carroll, SM., Ingraham, J.B., Wang, J., Marx, C.J., and Springer, M. (2015) Galactose metabolic genes in yeast respond to a ratio of galactose and glucose. Proc Natl Acad Sci U S A 112(5): 1636-1641.
(* Equal contribution, in alphabetical order)

Wang, J., Atolia, E., Hua, B., Savir, Y,. Escalante R.Springer, M. (2015) Cost-Benefit Tradeoff Underlies Natural Variation in Preparation for Nutrient Depletion ,PLoS Biology 13(1): e1002041.

Molecular recognition in presence of competition and noisy information channels

information channelPractically all biological systems rely on the ability of bio-molecules to specifically recognize each other. Examples are antibodies targeting antigens, regulatory proteins binding DNA and enzymes catalyzing their substrates. These and other molecular recognizers must locate and preferentially interact with their specific targets among a vast variety of molecules that are often structurally similar. This task is further complicated by the inherent noise in the biochemical environment, whose magnitude is comparable with that of the non-covalent binding interactions.

This raises the question of how such a remarkable discrimination is being achieved?cell_ribo

Signal detection theory deals with decision making under uncertainty and provides  quantitative measures to estimate the quality of the decision. We use this framework to derive a measure for the discrimination ability of molecular recognizers and derive the energy landscape that provides optimal discrimination between competing substrates .

We show that measured landscapes of crucial process such as codon recognition by the ribosome and homologous recombination are indeed sculpted in this way.

Our results suggest a general design principle, termed conformational proofreading in which introducing a structural mismatch between the recognizer and its target enhances the quality of detection

Savir, Y, Kagan, J., Tlusty, T. (2015) Binding of transcription factors adapts to resolve information-energy trade-off (in review, arxiv:1505.01215)molecular cell HR

Savir, Y.. and  Tlusty, T. (2013) The ribosome as an optimal decoder: a lesson in molecular recognition. Cell153 (2)

Savir, Y., and Tlusty, T. (2010). RecA mediated homologous search as a nearly optimal signal detection process, Mol. Cell, (see also cover image and preview in Mol. Cell)

Savir, Y., and Tlusty, T. (2009). Molecular Recognition as an Information Channel: The Role of Conformational Changes, CISS 2009,

Savir, Y., and Tlusty, T. (2008). Optimal Design of a Molecular Recognizer : Molecular Recognition as a Bayesian Signal Detection Problem. IEEE J Sel Topics Signal Process

Savir, Y., and Tlusty, T. (2007). Conformational proofreading: the impact of conformational changes on the specificity of molecular recognition. PLoS ONE (see also review in Nature)

Optimality, tradeoffs and constraint in protein evolution

What shapes the landscape on which proteins evolvrate vs specificty rubiscoe? What is the role of balancing sometimes opposite demands such as speed vs. specificity?

We examine these questions by analyzing the measured kinetic parameters of Rubisco, probably the most abundant protein in the biosphere, performs an essential part in the process of carbon fixation through photosynthesis. We analyzed the measured kinetic parameters of Rubisco from various organisms living in various environments and suggest that the evolution of Rubisco is confined toan effectively 1D landscape, which is manifested in simple power law correlations between its kinetic parameters. Within this 1D landscape, which may represent biochemical and structural constraints, Rubisco appears to be tuned to the intracellular environment in which it resides such that the net photosynthesis rate is nearly optimal. Rubisco appears as an experimentally testable example for the evolution of proteins subject both to strong selection pressure and to biochemical constraints.

Savir, Y., Noor, E., Milo, R., and Tlusty, T. (2010). Cross-species analysis traces adaptation of Rubisco toward optimality in a low-dimensional landscape. Proc Natl Acad Sci U S A

Bar-Even, A., Noor, E., Savir, Y., Liebermeister, W., Davidi, D., Tawfik, D. S., & Milo, R. (2011). The moderately efficient enzyme: evolutionary and physicochemical trends shaping enzyme parameters. Biochemistry, 50(21)

Cellular communication and T-Cell activationextracellualr feedback T cells

We study interactions between polyclonal activated T cells that are mediated by IL-2 extracellular feedback as a model system. we show that extracellular feedback can give rise to opposite outcomes: competition or cooperation between interacting T cells, depending on their relative levels of activation. Furthermore, the outcome of the interaction also depends on the relative timing of activation of the cells. A critical time window exists after which a cell that has been more strongly activated nevertheless cannot exclude an inferior competitor.

We propose extracellular feedback as a general mechanism that can balance speed and accuracy – choosing the most suitable responders out of a polyclonal population under the clock of an escalating threat

Savir, Y.*, Waysbrot, N,*. Antebi, YE., Tlusty, T. Friedman, N. (2012). Balancing speed and accuracy of polyclonal T cell activation: a role for extracellular feedback. BMC Syst Biol, 27;(6)

* Equal contribution, in alphabetical order