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The emerging regulatory potential of SCFMet30 -mediated polyubiquitination and proteolysis of the Met4 transcriptional activator.

Chandrasekaran S, Skowyra D - Cell Div (2008)

Bottom Line: We revisit this model in light of the growing evidence that SCFMet30 can also activate Met4.The notion that Met4 can be inhibited or activated depending on the sulfur metabolite context is not new, but for the first time both aspects have been linked to SCFMet30, creating an interesting regulatory paradigm in which polyubiquitination and proteolysis of a single transcriptional activator can play different roles depending on context.We discuss the emerging molecular basis and the implications of this new regulatory phenomenon.

View Article: PubMed Central - HTML - PubMed

Affiliation: Edward A, Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St, Louis, MO, 63104, USA. skowyrad@slu.edu.

ABSTRACT
The yeast SCFMet30 ubiquitin ligase plays a critical role in cell division by regulating the Met4 transcriptional activator of genes that control the uptake and assimilation of sulfur into methionine and S-adenosyl-methionine. The initial view on how SCFMet30 performs its function has been driven by the assumption that SCFMet30 acts exclusively as Met4 inhibitor when high levels of methionine drive an accumulation of cysteine. We revisit this model in light of the growing evidence that SCFMet30 can also activate Met4. The notion that Met4 can be inhibited or activated depending on the sulfur metabolite context is not new, but for the first time both aspects have been linked to SCFMet30, creating an interesting regulatory paradigm in which polyubiquitination and proteolysis of a single transcriptional activator can play different roles depending on context. We discuss the emerging molecular basis and the implications of this new regulatory phenomenon.

No MeSH data available.


Related in: MedlinePlus

Functional domains in the Met4 protein. (A). Functional domains in the Met4 protein: ACT (activation domain), IR (Inhibitory Region), AUX (Auxiliary Region), BD (Basic Domain), LZ (Leucine Zipper), UIM (Ubiquitin Interacting Motif). Blue outlines functions associated with the domains. Green arrows point to cofactors interacting with the domains. Cofactors with a regulatory role are marked in green. DNA binding cofactors are marked in gray. Red horizontal arrows emphasize that new interactions could be created between cofactors when they bind to Met4. (B). Scheme illustrating dissociation of Met4 homodimers by SCFMet30. See text for details.
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Figure 2: Functional domains in the Met4 protein. (A). Functional domains in the Met4 protein: ACT (activation domain), IR (Inhibitory Region), AUX (Auxiliary Region), BD (Basic Domain), LZ (Leucine Zipper), UIM (Ubiquitin Interacting Motif). Blue outlines functions associated with the domains. Green arrows point to cofactors interacting with the domains. Cofactors with a regulatory role are marked in green. DNA binding cofactors are marked in gray. Red horizontal arrows emphasize that new interactions could be created between cofactors when they bind to Met4. (B). Scheme illustrating dissociation of Met4 homodimers by SCFMet30. See text for details.

Mentions: Analysis of Met4 function has first helped to establish the view that transcriptional activation is driven not only by binding of specific cofactors to activating sequences located upstream of promoters, but also by the assembly of highly specific multi-protein complexes (reviewed in [1]). Unlike most other basic leucine zipper proteins, Met4 cannot bind DNA directly due to an unusual arrangement of its basic domain (Fig. 2A, BD*), explaining why its recruitment to specific promoters depends on an interaction with the DNA binding cofactors Cbf1 and/or Met31/32 (Fig. 2A, gray). The benefits of the interaction are mutual, as Met4 regulates DNA binding by Cbf1 in a manner dependent on an interaction with the basic leucine zipper cofactor Met28 (Fig. 2A, green), which does not bind Cbf1 directly and only weakly interacts with DNA [2]. A Met28-dependent conformational transition in Met4 could thus be responsible for the stimulation of DNA binding by Cbf1. The regulatory nature of the Met4-Met28 interaction is further illustrated by the finding that more Met28 binds Met4 during growth in a methionine-free medium [3], when the Met4-controlled MET and SAM genes are expressed, correlating with the recruitment of SAGA and mediator complexes [4]. Met32 can co-purify with Cbf1/Met4/Met28 located at promoters that do not contain the specific Met32-binding element [5], suggesting that Met32, like Met28, can play a yet unidentified, DNA binding independent regulatory role.


The emerging regulatory potential of SCFMet30 -mediated polyubiquitination and proteolysis of the Met4 transcriptional activator.

Chandrasekaran S, Skowyra D - Cell Div (2008)

Functional domains in the Met4 protein. (A). Functional domains in the Met4 protein: ACT (activation domain), IR (Inhibitory Region), AUX (Auxiliary Region), BD (Basic Domain), LZ (Leucine Zipper), UIM (Ubiquitin Interacting Motif). Blue outlines functions associated with the domains. Green arrows point to cofactors interacting with the domains. Cofactors with a regulatory role are marked in green. DNA binding cofactors are marked in gray. Red horizontal arrows emphasize that new interactions could be created between cofactors when they bind to Met4. (B). Scheme illustrating dissociation of Met4 homodimers by SCFMet30. See text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2526995&req=5

Figure 2: Functional domains in the Met4 protein. (A). Functional domains in the Met4 protein: ACT (activation domain), IR (Inhibitory Region), AUX (Auxiliary Region), BD (Basic Domain), LZ (Leucine Zipper), UIM (Ubiquitin Interacting Motif). Blue outlines functions associated with the domains. Green arrows point to cofactors interacting with the domains. Cofactors with a regulatory role are marked in green. DNA binding cofactors are marked in gray. Red horizontal arrows emphasize that new interactions could be created between cofactors when they bind to Met4. (B). Scheme illustrating dissociation of Met4 homodimers by SCFMet30. See text for details.
Mentions: Analysis of Met4 function has first helped to establish the view that transcriptional activation is driven not only by binding of specific cofactors to activating sequences located upstream of promoters, but also by the assembly of highly specific multi-protein complexes (reviewed in [1]). Unlike most other basic leucine zipper proteins, Met4 cannot bind DNA directly due to an unusual arrangement of its basic domain (Fig. 2A, BD*), explaining why its recruitment to specific promoters depends on an interaction with the DNA binding cofactors Cbf1 and/or Met31/32 (Fig. 2A, gray). The benefits of the interaction are mutual, as Met4 regulates DNA binding by Cbf1 in a manner dependent on an interaction with the basic leucine zipper cofactor Met28 (Fig. 2A, green), which does not bind Cbf1 directly and only weakly interacts with DNA [2]. A Met28-dependent conformational transition in Met4 could thus be responsible for the stimulation of DNA binding by Cbf1. The regulatory nature of the Met4-Met28 interaction is further illustrated by the finding that more Met28 binds Met4 during growth in a methionine-free medium [3], when the Met4-controlled MET and SAM genes are expressed, correlating with the recruitment of SAGA and mediator complexes [4]. Met32 can co-purify with Cbf1/Met4/Met28 located at promoters that do not contain the specific Met32-binding element [5], suggesting that Met32, like Met28, can play a yet unidentified, DNA binding independent regulatory role.

Bottom Line: We revisit this model in light of the growing evidence that SCFMet30 can also activate Met4.The notion that Met4 can be inhibited or activated depending on the sulfur metabolite context is not new, but for the first time both aspects have been linked to SCFMet30, creating an interesting regulatory paradigm in which polyubiquitination and proteolysis of a single transcriptional activator can play different roles depending on context.We discuss the emerging molecular basis and the implications of this new regulatory phenomenon.

View Article: PubMed Central - HTML - PubMed

Affiliation: Edward A, Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St, Louis, MO, 63104, USA. skowyrad@slu.edu.

ABSTRACT
The yeast SCFMet30 ubiquitin ligase plays a critical role in cell division by regulating the Met4 transcriptional activator of genes that control the uptake and assimilation of sulfur into methionine and S-adenosyl-methionine. The initial view on how SCFMet30 performs its function has been driven by the assumption that SCFMet30 acts exclusively as Met4 inhibitor when high levels of methionine drive an accumulation of cysteine. We revisit this model in light of the growing evidence that SCFMet30 can also activate Met4. The notion that Met4 can be inhibited or activated depending on the sulfur metabolite context is not new, but for the first time both aspects have been linked to SCFMet30, creating an interesting regulatory paradigm in which polyubiquitination and proteolysis of a single transcriptional activator can play different roles depending on context. We discuss the emerging molecular basis and the implications of this new regulatory phenomenon.

No MeSH data available.


Related in: MedlinePlus