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1.
PLoS Genet ; 19(5): e1010745, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37196001

RESUMEN

Glucose is the preferred carbon source for most eukaryotes, and the first step in its metabolism is phosphorylation to glucose-6-phosphate. This reaction is catalyzed by hexokinases or glucokinases. The yeast Saccharomyces cerevisiae encodes three such enzymes, Hxk1, Hxk2, and Glk1. In yeast and mammals, some isoforms of this enzyme are found in the nucleus, suggesting a possible moonlighting function beyond glucose phosphorylation. In contrast to mammalian hexokinases, yeast Hxk2 has been proposed to shuttle into the nucleus in glucose-replete conditions, where it reportedly moonlights as part of a glucose-repressive transcriptional complex. To achieve its role in glucose repression, Hxk2 reportedly binds the Mig1 transcriptional repressor, is dephosphorylated at serine 15 and requires an N-terminal nuclear localization sequence (NLS). We used high-resolution, quantitative, fluorescent microscopy of live cells to determine the conditions, residues, and regulatory proteins required for Hxk2 nuclear localization. Countering previous yeast studies, we find that Hxk2 is largely excluded from the nucleus under glucose-replete conditions but is retained in the nucleus under glucose-limiting conditions. We find that the Hxk2 N-terminus does not contain an NLS but instead is necessary for nuclear exclusion and regulating multimerization. Amino acid substitutions of the phosphorylated residue, serine 15, disrupt Hxk2 dimerization but have no effect on its glucose-regulated nuclear localization. Alanine substation at nearby lysine 13 affects dimerization and maintenance of nuclear exclusion in glucose-replete conditions. Modeling and simulation provide insight into the molecular mechanisms of this regulation. In contrast to earlier studies, we find that the transcriptional repressor Mig1 and the protein kinase Snf1 have little effect on Hxk2 localization. Instead, the protein kinase Tda1 regulates Hxk2 localization. RNAseq analyses of the yeast transcriptome dispels the idea that Hxk2 moonlights as a transcriptional regulator of glucose repression, demonstrating that Hxk2 has a negligible role in transcriptional regulation in both glucose-replete and limiting conditions. Our studies define a new model of cis- and trans-acting regulators of Hxk2 dimerization and nuclear localization. Based on our data, the nuclear translocation of Hxk2 in yeast occurs in glucose starvation conditions, which aligns well with the nuclear regulation of mammalian orthologs. Our results lay the foundation for future studies of Hxk2 nuclear activity.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Glucosa/metabolismo , Hexoquinasa/genética , Hexoquinasa/metabolismo , Proteínas Quinasas/metabolismo , Proteínas Represoras/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Serina/genética , Serina/metabolismo , Factores de Transcripción/metabolismo
2.
PLoS Comput Biol ; 18(3): e1009929, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35235554

RESUMEN

Glucose is central to many biological processes, serving as an energy source and a building block for biosynthesis. After glucose enters the cell, hexokinases convert it to glucose-6-phosphate (Glc-6P) for use in anaerobic fermentation, aerobic oxidative phosphorylation, and the pentose-phosphate pathway. We here describe a genetic screen in Saccharomyces cerevisiae that generated a novel spontaneous mutation in hexokinase-2, hxk2G238V, that confers resistance to the toxic glucose analog 2-deoxyglucose (2DG). Wild-type hexokinases convert 2DG to 2-deoxyglucose-6-phosphate (2DG-6P), but 2DG-6P cannot support downstream glycolysis, resulting in a cellular starvation-like response. Curiously, though the hxk2G238V mutation encodes a loss-of-function allele, the affected amino acid does not interact directly with bound glucose, 2DG, or ATP. Molecular dynamics simulations suggest that Hxk2G238V impedes sugar binding by altering the protein dynamics of the glucose-binding cleft, as well as the large-scale domain-closure motions required for catalysis. These findings shed new light on Hxk2 dynamics and highlight how allosteric changes can influence catalysis, providing new structural insights into this critical regulator of carbohydrate metabolism. Given that hexokinases are upregulated in some cancers and that 2DG and its derivatives have been studied in anti-cancer trials, the present work also provides insights that may apply to cancer biology and drug resistance.


Asunto(s)
Desoxiglucosa , Hexoquinasa , Desoxiglucosa/metabolismo , Glucosa/metabolismo , Hexoquinasa/genética , Hexoquinasa/metabolismo , Mutación , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
3.
PLoS Genet ; 17(9): e1009800, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34555030

RESUMEN

Previous studies of adaptation to the glucose analog, 2-deoxyglucose, by Saccharomyces cerevisiae have utilized haploid cells. In this study, diploid cells were used in the hope of identifying the distinct genetic mechanisms used by diploid cells to acquire drug resistance. While haploid cells acquire resistance to 2-deoxyglucose primarily through recessive alleles in specific genes, diploid cells acquire resistance through dominant alleles, haploinsufficiency, gene duplication and aneuploidy. Dominant-acting, missense alleles in all three subunits of yeast AMP-activated protein kinase confer resistance to 2-deoxyglucose. Dominant-acting, nonsense alleles in the REG1 gene, which encodes a negative regulator of AMP-activated protein kinase, confer 2-deoxyglucose resistance through haploinsufficiency. Most of the resistant strains isolated in this study achieved resistance through aneuploidy. Cells with a monosomy of chromosome 4 are resistant to 2-deoxyglucose. While this genetic strategy comes with a severe fitness cost, it has the advantage of being readily reversible when 2-deoxyglucose selection is lifted. Increased expression of the two DOG phosphatase genes on chromosome 8 confers resistance and was achieved through trisomies and tetrasomies of that chromosome. Finally, resistance was also mediated by increased expression of hexose transporters, achieved by duplication of a 117 kb region of chromosome 4 that included the HXT3, HXT6 and HXT7 genes. The frequent use of aneuploidy as a genetic strategy for drug resistance in diploid yeast and human tumors may be in part due to its potential for reversibility when selection pressure shifts.


Asunto(s)
Alelos , Aneuploidia , Diploidia , Farmacorresistencia Fúngica/genética , Duplicación de Gen , Genes Dominantes , Haploinsuficiencia , Saccharomyces cerevisiae/genética , Cromosomas Fúngicos , Desoxiglucosa/farmacología , Mutación , Saccharomyces cerevisiae/efectos de los fármacos , Secuenciación Completa del Genoma
4.
PLoS Genet ; 16(7): e1008484, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32673313

RESUMEN

Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. Missense alleles of the HXK2, REG1, GLC7 and SNF1 genes were shown to confer significant resistance to 2-deoxyglucose and all had the potential to alter the activity and or target selection of the Snf1 kinase signaling pathway. All three missense alleles in HXK2 resulted in significantly reduced catalytic activity. Addition of 2DG promotes endocytosis of the glucose transporter Hxt3. All but one of the 2DG-resistant strains reduced the 2DG-mediated hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both the DOG1 and DOG2 mRNA was elevated after treatment with 2-deoxyglucose but induction of these genes is not associated with 2DG-resistance. RNAseq analysis of the transcriptional response to 2DG showed large scale, genome-wide changes in mRNA abundance that were greatly reduced in the 2DG resistant strains. These findings suggest the common adaptive response to 2DG is to limit the magnitude of the response. Genetic studies of 2DG resistance using the dominant SNF1-G53R allele in cells that are genetically compromised in both the endocytosis and DOG pathways suggest that at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.


Asunto(s)
Metabolismo Energético/genética , Glucosa/metabolismo , Hexoquinasa/genética , Monoéster Fosfórico Hidrolasas/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Saccharomyces cerevisiae/genética , Desoxiglucosa/efectos adversos , Desoxiglucosa/farmacología , Endocitosis/efectos de los fármacos , Endocitosis/genética , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Humanos , Mutación/genética , Proteína Fosfatasa 1/genética , ARN Mensajero/genética , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Transducción de Señal/efectos de los fármacos , Secuenciación Completa del Genoma
5.
Cell Signal ; 28(12): 1881-1893, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27592031

RESUMEN

Saccharomyces cerevisiae express three isoforms of Snf1 kinase that differ by which ß subunit is present, Gal83, Sip1 or Sip2. Here we investigate the abundance, activation, localization and signaling specificity of the three Snf1 isoforms. The relative abundance of these isoforms was assessed by quantitative immunoblotting using two different protein extraction methods and by fluorescence microscopy. The Gal83 containing isoform is the most abundant in all assays while the abundance of the Sip1 and Sip2 isoforms is typically underestimated especially in glass-bead extractions. Earlier studies to assess Snf1 isoform function utilized gene deletions as a means to inactivate specific isoforms. Here we use point mutations in Gal83 and Sip2 and a 17 amino acid C-terminal truncation of Sip1 to inactivate specific isoforms without affecting their abundance or association with the other subunits. The effect of low glucose and alkaline stresses was examined for two Snf1 phosphorylation substrates, the Mig1 and Mig2 proteins. Any of the three isoforms was capable of phosphorylating Mig1 in response to glucose stress. In contrast, the Gal83 isoform of Snf1 was both necessary and sufficient for the phosphorylation of the Mig2 protein in response to alkaline stress. Alkaline stress led to the activation of all three isoforms yet only the Gal83 isoform translocates to the nucleus and phosphorylates Mig2. Deletion of the SAK1 gene blocked nuclear translocation of Gal83 and signaling to Mig2. These data strongly support the idea that Snf1 signaling specificity is mediated by localization of the different Snf1 isoforms.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Álcalis/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Subunidades de Proteína/metabolismo , Saccharomyces cerevisiae/enzimología , Estrés Fisiológico/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Secuencia Conservada , Activación Enzimática , Glucosa/farmacología , Histidina/metabolismo , Isoenzimas/metabolismo , Cinética , Proteínas Mutantes/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/química , Subunidades de Proteína/química , Transporte de Proteínas/efectos de los fármacos , Saccharomyces cerevisiae/efectos de los fármacos , Especificidad por Sustrato/efectos de los fármacos
6.
Biochim Biophys Acta ; 1864(11): 1518-28, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27524664

RESUMEN

The AMP-activated protein kinase is a metabolic regulator that transduces information about energy and nutrient availability. In yeast, the AMP-activated protein kinase, called Snf1, is activated when energy and nutrients are scarce. Earlier studies have demonstrated that activation of Snf1 requires the phosphorylation of the activation loop on threonine 210. Here we examined the regulation of Snf1 kinase activity in response to phosphorylation at other sites. Phosphoproteomic studies have identified numerous phosphorylation sites within the Snf1 kinase enzyme. We made amino acid substitutions in the Snf1 protein that were either non-phosphorylatable (serine to alanine) or phospho-mimetic (serine to glutamate) and examined the effects of these changes on Snf1 kinase function in vivo and on its catalytic activity in vitro. We found that changes to most of the phosphorylation sites had no effect on Snf1 kinase function. However, changes to serine 214, a site within the kinase activation loop, inhibited Snf1 kinase activity. Snf1-activating kinase 1 still phosphorylates Snf1-S214E on threonine 210 but the S214E enzyme is non-functional in vivo and catalytically inactive in vitro. We conclude that yeast have developed two distinct pathways for down-regulating Snf1 activity. The first is through direct dephosphorylation of the conserved activation loop threonine. The second is through phosphorylation of serine 214.


Asunto(s)
Fosfoproteínas/química , Proteínas Serina-Treonina Quinasas/química , Saccharomyces cerevisiae/enzimología , Serina/química , Treonina/química , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Clonación Molecular , Secuencia Conservada , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Modelos Moleculares , Mutación , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilación , Dominios Proteicos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Secundaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/genética , Alineación de Secuencia , Serina/metabolismo , Treonina/metabolismo
7.
Mol Cell Biol ; 35(6): 939-55, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25547292

RESUMEN

The glucose analog 2-deoxyglucose (2DG) inhibits the growth of Saccharomyces cerevisiae and human tumor cells, but its modes of action have not been fully elucidated. Yeast cells lacking Snf1 (AMP-activated protein kinase) are hypersensitive to 2DG. Overexpression of either of two low-affinity, high-capacity glucose transporters, Hxt1 and Hxt3, suppresses the 2DG hypersensitivity of snf1Δ cells. The addition of 2DG or the loss of Snf1 reduces HXT1 and HXT3 expression levels and stimulates transporter endocytosis and degradation in the vacuole. 2DG-stimulated trafficking of Hxt1 and Hxt3 requires Rod1/Art4 and Rog3/Art7, two members of the α-arrestin trafficking adaptor family. Mutations in ROD1 and ROG3 that block binding to the ubiquitin ligase Rsp5 eliminate Rod1- and Rog3-mediated trafficking of Hxt1 and Hxt3. Genetic analysis suggests that Snf1 negatively regulates both Rod1 and Rog3, but via different mechanisms. Snf1 activated by 2DG phosphorylates Rod1 but fails to phosphorylate other known targets, such as the transcriptional repressor Mig1. We propose a novel mechanism for 2DG-induced toxicity whereby 2DG stimulates the modification of α-arrestins, which promote glucose transporter internalization and degradation, causing glucose starvation even when cells are in a glucose-rich environment.


Asunto(s)
Arrestina/metabolismo , Desoxiglucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Endocitosis/fisiología , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Glucosa/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Transporte de Proteínas/fisiología , Ubiquitina/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo
8.
Genetics ; 198(2): 635-46, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25116136

RESUMEN

Aerobic glycolysis is a metabolic pathway utilized by human cancer cells and also by yeast cells when they ferment glucose to ethanol. Both cancer cells and yeast cells are inhibited by the presence of low concentrations of 2-deoxyglucose (2DG). Genetic screens in yeast used resistance to 2-deoxyglucose to identify a small set of genes that function in regulating glucose metabolism. A recent high throughput screen for 2-deoxyglucose resistance identified a much larger set of seemingly unrelated genes. Here, we demonstrate that these newly identified genes do not in fact confer significant resistance to 2-deoxyglucose. Further, we show that the relative toxicity of 2-deoxyglucose is carbon source dependent, as is the resistance conferred by gene deletions. Snf1 kinase, the AMP-activated protein kinase of yeast, is required for 2-deoxyglucose resistance in cells growing on glucose. Mutations in the SNF1 gene that reduce kinase activity render cells hypersensitive to 2-deoxyglucose, while an activating mutation in SNF1 confers 2-deoxyglucose resistance. Snf1 kinase activated by 2-deoxyglucose does not phosphorylate the Mig1 protein, a known Snf1 substrate during glucose limitation. Thus, different stimuli elicit distinct responses from the Snf1 kinase.


Asunto(s)
Desoxiglucosa/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Farmacorresistencia Fúngica , Epistasis Genética , Eliminación de Gen , Viabilidad Microbiana/efectos de los fármacos , Viabilidad Microbiana/genética , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/genética , Proteínas Represoras/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transducción de Señal
9.
J Biol Chem ; 288(1): 89-98, 2013 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-23184934

RESUMEN

The AMP-activated protein kinase (AMPK) is a conserved signaling molecule in a pathway that maintains adenosine triphosphate homeostasis. Recent studies have suggested that low energy adenylate ligands bound to one or more sites in the γ subunit of AMPK promote the formation of an active, phosphatase-resistant conformation. We propose an alternative model in which the kinase domain association with the heterotrimer core results in activation of the kinase catalytic activity, whereas low energy adenylate ligands bound in the kinase active site promote phosphatase resistance. Purified Snf1 α subunit with a conservative, single amino acid substitution in the kinase domain is protected from dephosphorylation by adenosine diphosphate in the complete absence of the ß and γ subunits. Staurosporine, a compound known to bind to the active site of many protein kinases, mediates strong protection from dephosphorylation to yeast and mammalian AMPK enzymes. The analog-sensitive Snf1-I132G protein but not wild type Snf1 exhibits protection from dephosphorylation when bound by the adenosine analog 2NM-PP1 in vitro and in vivo. These data demonstrate that ligand binding to the Snf1 active site can mediate phosphatase resistance. Finally, Snf1 kinase with an amino acid substitution at the interface of the kinase domain and the heterotrimer core exhibits normal regulation of phosphorylation in vivo but greatly reduced Snf1 kinase activity, supporting a model in which kinase domain association with the heterotrimer core is needed for kinase activation.


Asunto(s)
Proteínas Quinasas Activadas por AMP/química , Regulación Enzimológica de la Expresión Génica , Schizosaccharomyces/metabolismo , Adenosina Difosfato/química , Animales , Dominio Catalítico , Inhibidores Enzimáticos/farmacología , Proteínas Fúngicas/química , Humanos , Cinética , Ligandos , Modelos Moleculares , Conformación Molecular , Mutación , Fosforilación , Unión Proteica , Proteínas Serina-Treonina Quinasas/química , Estructura Terciaria de Proteína , Ratas , Schizosaccharomyces/química , Transducción de Señal , Estaurosporina/farmacología , Especificidad por Sustrato
10.
J Biol Chem ; 286(52): 44532-41, 2011 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-22065577

RESUMEN

Members of the AMP-activated protein kinase (AMPK) family are activated by phosphorylation at a conserved threonine residue in the activation loop of the kinase domain. Mammalian AMPK adopts a phosphatase-resistant conformation that is stabilized by binding low energy adenylate molecules. Similarly, binding of ADP to the Snf1 complex, yeast AMPK, protects the kinase from dephosphorylation. Here, we determined the nucleotide specificity of the ligand-mediated protection from dephosphorylation and demonstrate the subunit and domain requirements for this reaction. Protection from dephosphorylation was highly specific for adenine nucleotides, with ADP being the most effective ligand for mediating protection. The full-length α subunit (Snf1) was not competent for ADP-mediated protection, confirming the requirement for the regulatory ß and γ subunits. However, Snf1 heterotrimeric complexes that lacked either the glycogen-binding domain of Gal83 or the linker region of the α subunit were competent for ADP-mediated protection. In contrast, adenylate-mediated protection of recombinant human AMPK was abolished when a portion of the linker region containing the α-hook domain was deleted. Therefore, the exact means by which the different adenylate nucleotides are distinguished by the Snf1 enzyme may differ compared with its mammalian ortholog.


Asunto(s)
Adenosina Difosfato/metabolismo , Adenosina Monofosfato/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Quinasas de la Proteína-Quinasa Activada por el AMP , Adenosina Difosfato/química , Adenosina Difosfato/genética , Adenosina Monofosfato/química , Adenosina Monofosfato/genética , Dominio Catalítico , Humanos , Fosforilación/fisiología , Proteínas Quinasas/química , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Estructura Secundaria de Proteína , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética
11.
Eukaryot Cell ; 10(12): 1628-36, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22002657

RESUMEN

The phosphorylation status of the Snf1 activation loop threonine is determined by changes in the rate of its dephosphorylation, catalyzed by the yeast PP1 phosphatase Glc7 in complex with the Reg1 protein. Previous studies have shown that Reg1 can associate with both Snf1 and Glc7, suggesting substrate binding as a mechanism for Reg1-mediated targeting of Glc7. In this study, the association of Reg1 with the three Snf1 isoforms was measured by two-hybrid analysis and coimmunoprecipitation. We found that Reg1 association with Snf1 occurred almost exclusively with the Gal83 isoform of the Snf1 complex. Nonetheless, Reg1 plays an important role in determining the phosphorylation status of all three Snf1 isoforms. We found that the rate of dephosphorylation for isoforms of Snf1 did not correlate with the amount of associated Reg1 protein. Functional chimeric ß subunits containing residues from Gal83 and Sip2 were used to map the residues needed to promote Reg1 association with the N-terminal 150 residues of Gal83. The Gal83 isoform of Snf1 is the only isoform capable of nuclear localization. A Gal83-Sip2 chimera containing the first 150 residues of Gal83 was able to associate with the Reg1 protein but did not localize to the nucleus. Therefore, nuclear localization is not required for Reg1 association. Taken together, these data indicate that the ability of Reg1 to promote the dephosphorylation of Snf1 is not directly related to the strength of its association with the Snf1 complex.


Asunto(s)
Proteína Fosfatasa 1/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Represoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiología , Saccharomyces cerevisiae/enzimología , Proteínas Fluorescentes Verdes/metabolismo , Isoenzimas/metabolismo , Señales de Localización Nuclear , Fosforilación , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteína Fosfatasa 1/metabolismo , Transporte de Proteínas , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/química , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/química , Transactivadores/metabolismo , Técnicas del Sistema de Dos Híbridos
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