A steady‐state modeling approach to validate an <i>in vivo</i> mechanism of the GAL regulatory network in <i>Saccharomyces cerevisiae</i>

Verma, Malkhey; Bhat, Paike Jayadeva; Bhartiya, Sharad; Venkatesh, Kareenhalli V.

doi:10.1111/j.1432-1033.2004.04344.x

Cited by 16 publications

(16 citation statements)

References 34 publications

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“…1; [33]). Similar conclusions have been reached through mathematical simulations and steadystate modeling [63,64]. These suggest that stochastic variations in the nuclear concentrations of the repressor Gal80p may account for the activation of the GAL genetic switch and that a Gal3p-dependent cytosolic sequestration of Gal80p may subsequently shift Gal80p equilibrium towards this compartment.…”

Section: Induction By Galactosesupporting

confidence: 72%

A comparative analysis of the genetic switch between not-so-distant cousins: versus

Rubio‐Texeira

2005

FEMS Yeast Research

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Despite their close phylogenetic relationship, Kluyveromyces lactis and Saccharomyces cerevisiae have adapted their carbon utilization systems to different environments. Although they share identities in the arrangement, sequence and functionality of their GAL gene set, both yeasts have evolved important differences in the GAL genetic switch in accordance to their relative preference for the utilization of galactose as a carbon source. This review provides a comparative overview of the GAL-specific regulatory network in S. cerevisiae and K. lactis, discusses the latest models proposed to explain the transduction of the galactose signal, and describes some of the particularities that both microorganisms display in their regulatory response to different carbon sources. Emphasis is placed on the potential for improved strategies in biotechnological applications using yeasts.

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Section: Induction By Galactosesupporting

confidence: 72%

A comparative analysis of the genetic switch between not-so-distant cousins: versus

Rubio‐Texeira

2005

FEMS Yeast Research

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“…The latter have shown that formation of such a complex results in high switching efficiency even when KlGal1-KlGal80 affinities are much lower than those of the KlGal4-KlGal80 complex. Any previous descriptions of the galactose switch in mathematical terms assumed comparable affinities of Gal80 to Gal3 and Gal4 (61,62), because so far experimental data allowing the calculation of K D values for the Gal1/Gal3-Gal80 complex have been lacking. The combination of experiments and mathematical modeling has enabled us to identify modes of interactions between the regulatory proteins as crucially important factors for the operation of the molecular switch.…”

Section: Discussionmentioning

confidence: 99%

The Galactose Switch in Kluyveromyces lactis Depends on Nuclear Competition between Gal4 and Gal1 for Gal80 Binding

Anders

Lilie

Franke

et al. 2006

Journal of Biological Chemistry

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The Gal4 protein represents a universally functional transcription activator, which in yeast is regulated by protein-protein interaction of its transcription activation domain with the inhibitor Gal80. Gal80 inhibition is relieved via galactose-mediated Gal80-Gal1-Gal3 interaction. The Gal4-Gal80-Gal1/3 regulatory module is conserved between Saccharomyces cerevisiae and Kluyveromyces lactis. Here we demonstrate that K. lactis Gal80 (KlGal80) is a nuclear protein independent of the Gal4 activity status, whereas KlGal1 is detected throughout the entire cell, which implies that KlGal80 and KlGal1 interact in the nucleus. Consistently KlGal1 accumulates in the nucleus upon KlGAL80 overexpression. Furthermore, we show that the KlGal80-KlGal1 interaction blocks the galactokinase activity of KlGal1 and is incompatible with KlGal80-KlGal4-AD interaction. Thus, we propose that dissociation of KlGal80 from the AD forms the basis of KlGal4 activation in K. lactis. Quantitation of the dissociation constants for the KlGal80 complexes gives a much lower affinity for KlGal1 as compared with Gal4. Mathematical modeling shows that with these affinities a switch based on competition between Gal1 and Gal4 for Gal80 binding is nevertheless efficient provided two monomeric Gal1 molecules interact with dimeric Gal80. Consistent with such a mechanism, analysis of the sedimentation behavior by analytical ultracentrifugation demonstrates the formation of a heterotetrameric KlGal80-KlGal1 complex of 2:2 stoichiometry.Regulation of transcription requires coupling of gene-specific transcription activators to regulatory signals. The galactose switch, which induces the synthesis of galactose metabolic enzymes in response to this sugar in the environment, serves as a textbook model of how such coupling can be achieved in a eukaryotic cell (for reviews see Refs.

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“…The other hypothesis suggests that Gal3p enters the nucleus and interacts with DNA–Gal4p–Gal80p complex. A comparison of the response of the models for each of the two mechanisms with experimental data suggests that the formation of the quaternary complex (D–Gal4p–Gal80p–Gal3p) in the nucleus does not occur in vivo 34. The model‐based rejection of the hypothesis of the formation of the quaternary complex is consistent with the observed subcellular localization of these proteins 29…”

Section: Elucidation Of System‐level Properties Of Gal Regulon Using mentioning

confidence: 58%

“…Steady‐state models have been reported for GAL system by considering interactions at equilibrium and applying molar balances to the different components 34. Equilibrium dissociation constants and total concentrations for various components are obtained by in vitro studies and represent constraints on the candidate models.…”

Section: Elucidation Of System‐level Properties Of Gal Regulon Using mentioning

confidence: 99%

Systems biology of GAL regulon in Saccharomyces cerevisiae

Pannala

Bhat

Bhartiya

et al. 2010

WIREs Mechanisms of Disease

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Evolutionary success of an organism depends on its ability to express or adapt to constantly changing environmental conditions. Saccharomyces cerevisiae has evolved an elaborate genetic circuit to regulate the expression of galactose-metabolizing enzymes in the presence of galactose but in the absence of glucose. The circuit possesses molecular mechanisms such as multiple binding sites, cooperativity, autoregulation, nucleocytoplasmic shuttling, and substrate sensing mechanism. Furthermore, the GAL system consists of two positive (activating) feedback and one negative (repressing) feedback loops. These individual mechanisms, elucidated through experimental approach, can be integrated to obtain a system-wide behavior. Mathematical models in conjunction with guided experiments have demonstrated system-level properties such as ultrasensitivity, memory, noise attenuation, rapid response, and sensitive response arising out of the molecular interactions. These system-level properties allow S. cerevisiae to adapt and grow in a galactose medium under noisy and changing environments. This review focuses on system-level models and properties of the GAL regulon.

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A steady‐state modeling approach to validate an in vivo mechanism of the GAL regulatory network in Saccharomyces cerevisiae

Cited by 16 publications

References 34 publications

A comparative analysis of the genetic switch between not-so-distant cousins: versus

A comparative analysis of the genetic switch between not-so-distant cousins: versus

The Galactose Switch in Kluyveromyces lactis Depends on Nuclear Competition between Gal4 and Gal1 for Gal80 Binding

Systems biology of GAL regulon in Saccharomyces cerevisiae

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