The Gal3p transducer of the <i>GAL</i> regulon interacts with the Gal80p repressor in its ligand-induced closed conformation

Lavy, Tali; Kumar, P. Rajesh; He, Hongzhen; Joshua‐Tor, Leemor

doi:10.1101/gad.182691.111

Cited by 43 publications

(92 citation statements)

References 47 publications

(62 reference statements)

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“…A GAL1-lucCP ϩ reporter gene was used in live-cell luciferase limiting and galactose-containing medium, GAL gene expression is induced with the help of the Gal3 inducer. Upon stimulation, Gal3 binds galactose and ATP, interrupts Gal80 inhibition of Gal4, and permits transcriptional activation (19)(20)(21). Gal4 additionally recruits chromatin-modifying complexes and mediator (22)(23)(24)(25)(26)(27) in order to efficiently induce GAL gene expression.…”

mentioning

confidence: 99%

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

Rienzo

Poveda-Huertes

Aydin

et al. 2015

Molecular and Cellular Biology

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c Cells respond to environmental stimuli by fine-tuned regulation of gene expression. Here we investigated the dose-dependent modulation of gene expression at high temporal resolution in response to nutrient and stress signals in yeast. The GAL1 activity in cell populations is modulated in a well-defined range of galactose concentrations, correlating with a dynamic change of histone remodeling and RNA polymerase II (RNAPII) association. This behavior is the result of a heterogeneous induction delay caused by decreasing inducer concentrations across the population. Chromatin remodeling appears to be the basis for the dynamic GAL1 expression, because mutants with impaired histone dynamics show severely truncated dose-response profiles. In contrast, the GRE2 promoter operates like a rapid off/on switch in response to increasing osmotic stress, with almost constant expression rates and exclusively temporal regulation of histone remodeling and RNAPII occupancy. The Gal3 inducer and the Hog1 mitogen-activated protein (MAP) kinase seem to determine the different dose-response strategies at the two promoters. Accordingly, GAL1 becomes highly sensitive and dose independent if previously stimulated because of residual Gal3 levels, whereas GRE2 expression diminishes upon repeated stimulation due to acquired stress resistance. Our analysis reveals important differences in the way dynamic signals create dose-sensitive gene expression outputs.C ells continuously adapt their protein composition to changing environmental conditions. The regulation of gene expression is one of the fundamental mechanisms to adjust the global protein repertoire of the cell in order to maintain cell function and integrity in response to environmental challenges. Budding yeast is a powerful model to unravel the modes of transcriptional adaptation at the levels both of specific genes and of the whole organism (1, 2). Additionally, the basic structure of the signaling cascades responding to environmental perturbations is conserved from yeast to humans. It implies the alteration of core kinase activities, which modulate the expression of defense genes through a range of specific transcription factors. Extensive knowledge which precisely describes the molecular machinery and its global impact on gene expression in response to many types of stress has accumulated (3-7). However, the vast majority of these studies are performed with harsh environmental insults and therefore saturating stimulation. As a consequence, only very limited information or approaches are available to understand how cells adapt their gene expression programs to small or gradual changes in their environment.It is assumed that cells have acquired mechanisms that ensure a transcriptional response which is finely adjusted according to the strength of the stress or stimulation. However, the nature of the signaling molecules which confer gradual transcription outputs remains to be determined in most cases. Fine-tuning of gene expression responses can occur with different purposes, and th...

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mentioning

confidence: 99%

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

Rienzo

Poveda-Huertes

Aydin

et al. 2015

Molecular and Cellular Biology

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“…The structures of Gal1, Gal3 and Gal3–Gal80 are known [20, 31]. Gal1 and Gal3 show 74% sequence identity and are structurally superimposable with a root mean square deviation of ~ 1.1 Angstroms (Figure S1A; refs 20, 31).…”

Section: Resultsmentioning

confidence: 99%

“…Gal1 and Gal3 show 74% sequence identity and are structurally superimposable with a root mean square deviation of ~ 1.1 Angstroms (Figure S1A; refs 20, 31). Aspartate 117 maps to the predicted interaction surface between Gal1 and Gal80.…”

Section: Resultsmentioning

confidence: 99%

Genetic and Epigenetic Strategies Potentiate Gal4 Activation to Enhance Fitness in Recently Diverged Yeast Species

Sood

Brickner

2017

Current Biology

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Summary Certain genes show rapid reactivation after several generations of repression, a conserved phenomenon called epigenetic transcriptional memory. Following previous growth in galactose, GAL gene transcriptional memory confers a strong fitness benefit in Saccharomyces cerevisiae adapting to growth in galactose for up to 8 generations. A genetic screen for mutants defective for GAL gene memory revealed new insights into the molecular mechanism, adaptive consequences and evolutionary history of memory. A point mutation in the Gal1 coactivator that disrupts the interaction with the Gal80 inhibitor specifically and completely disrupted memory. This mutation confirms that cytoplasmically-inherited Gal1 produced during previous growth in galactose directly interferes with Gal80 repression to promote faster induction of GAL genes. This mitotically heritable mode of regulation is recently evolved; in a diverged Saccharomyces species, GAL genes show constitutively faster activation due to genetically-encoded basal expression of Gal1. Thus, recently diverged species utilize either epigenetic or genetic strategies to regulate the same molecular mechanism. The screen also revealed that the central domain of the Gal4 transcription factor both regulates the stochasticity of GAL gene expression and potentiates stronger GAL gene activation in the presence of Gal1. The central domain is critical for GAL gene transcriptional memory; Gal4 lacking the central domain fails to potentiate GAL gene expression and is unresponsive to previous Gal1 expression.

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“…Further members of the superfamily have been discovered subsequently and these include Nacetylgalactosamine kinase (GALK2), galacturonic acid kinase, arabinose kinase and pantoate kinase [3][4][5][6][7]. Two non-enzymatic family members, the Caenorhabditis elegans sex-fate determining protein XOL-1 and Saccharomyces cerevisiae transcriptional regulator Gal3p, have also been recognized as family members [8][9][10]. Proteins in the family have three highly conserved motifs.…”

Section: Introduction: Galactokinasementioning

confidence: 99%

Galactokinase promiscuity: a question of flexibility?

McAuley

Kristiansson

Huang

et al. 2016

Biochemical Society Transactions

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Many eukaryotic regulatory proteins adopt distinct bound and unbound conformations, and use this structural flexibility to bind specifically to multiple partners. However, we lack an understanding of how an interface can select some ligands, but not others. Here, we present a molecular dynamics approach to identify and quantitatively evaluate the interactions responsible for this selective promiscuity. We apply this approach to the anticancer target PD-1 and its ligands PD-L1 and PD-L2. We discover that while unbound PD-1 exhibits a hard-to-drug hydrophilic interface, conserved specific triggers encoded in the cognate ligands activate a promiscuous binding pathway that reveals a flexible hydrophobic binding cavity. Specificity is then established by additional contacts that stabilize the PD-1 cavity into distinct bound-like modes. Collectively, our studies provide insight into the structural basis and evolution of multiple binding partners, and also suggest a biophysical approach to exploit innate binding pathways to drug seemingly undruggable targets.

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The Gal3p transducer of the GAL regulon interacts with the Gal80p repressor in its ligand-induced closed conformation

Cited by 43 publications

References 47 publications

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

Different Mechanisms Confer Gradual Control and Memory at Nutrient- and Stress-Regulated Genes in Yeast

Genetic and Epigenetic Strategies Potentiate Gal4 Activation to Enhance Fitness in Recently Diverged Yeast Species

Galactokinase promiscuity: a question of flexibility?

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