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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

The emerging molecular mechanism of Met4 regulation by SCFMet30. The mechanism of Met4 activation by SCFMet30 is based on the prediction that the formation of Met4 homodimers antagonizes proper assembly between Met4 and cofactors (A), and that the dissociation of Met4 homodimers by SCFMet30 (B, step 1) is necessary to stabilize and/or rearrange the protein-protein interactions within the Met4/Met28/Cbf1 complex, triggering its proper assembly (B). The low abundance of SCFMet30 suggests that proteolysis of the remaining Met4 molecule occupying SCFMet30 (B, step 1) is necessary for SCFMet30 recycling (B, step 2). As a result, 'two stepping' with SCFMet30" could be necessary for each round of Met4 activity at a promoter (all steps involving SCFMet30 are marked in blue). The stabilizing effect of cofactors on the SCFMet30-Met4 interaction ('tight complex', note exposure of the UIM domain in Met4) allows Met4 inhibition by polyubiquitination only (C), unless methionine (D) or cysteine (DREP) is available to destabilize the tight interaction between Met4 and SCFMet30, allowing Met4 proteolysis. Disassembly of the Met4 complex by the proteasome could link activation of methionine biosynthesis to cell division by releasing the DNA binding cofactors Cbf1 and Met31/32 from promoters (D), which, at least in the case of Cbf1, would make it available for its cell division role. Dissociation of Met4 prior to its proteolysis could protect the cofactors and SCFMet30 from effects of the proteasome-mediated disassembly (DREP), preventing Cbf1 and/or Met31/32 release. See text for details.
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Figure 3: The emerging molecular mechanism of Met4 regulation by SCFMet30. The mechanism of Met4 activation by SCFMet30 is based on the prediction that the formation of Met4 homodimers antagonizes proper assembly between Met4 and cofactors (A), and that the dissociation of Met4 homodimers by SCFMet30 (B, step 1) is necessary to stabilize and/or rearrange the protein-protein interactions within the Met4/Met28/Cbf1 complex, triggering its proper assembly (B). The low abundance of SCFMet30 suggests that proteolysis of the remaining Met4 molecule occupying SCFMet30 (B, step 1) is necessary for SCFMet30 recycling (B, step 2). As a result, 'two stepping' with SCFMet30" could be necessary for each round of Met4 activity at a promoter (all steps involving SCFMet30 are marked in blue). The stabilizing effect of cofactors on the SCFMet30-Met4 interaction ('tight complex', note exposure of the UIM domain in Met4) allows Met4 inhibition by polyubiquitination only (C), unless methionine (D) or cysteine (DREP) is available to destabilize the tight interaction between Met4 and SCFMet30, allowing Met4 proteolysis. Disassembly of the Met4 complex by the proteasome could link activation of methionine biosynthesis to cell division by releasing the DNA binding cofactors Cbf1 and Met31/32 from promoters (D), which, at least in the case of Cbf1, would make it available for its cell division role. Dissociation of Met4 prior to its proteolysis could protect the cofactors and SCFMet30 from effects of the proteasome-mediated disassembly (DREP), preventing Cbf1 and/or Met31/32 release. See text for details.

Mentions: These observations have two implications for the mechanism by which SCFMet30 regulates Met4. First, the dissociation of Met4 homodimers by SCFMet30 could be necessary to stabilize and/or rearrange the protein-protein interactions within the Met4/Met28/Cbf1 complex and thereby trigger its full functional potential (Fig. 3B), explaining the positive regulatory role of SCFMet30. Indeed, Met4 dimerization represents an interesting conundrum, as it depends on the LZ domain also implicated in binding to the basic leucine zipper (bZIP) regulatory protein Met28 and the basic helix-loop-helix (bHLH) DNA binding protein Cbf1 (Fig. 2A, LZ). As such, Met4 dimerization could antagonize proper assembly and function of the Met4/Cbf1/Met28 complex.


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

Chandrasekaran S, Skowyra D - Cell Div (2008)

The emerging molecular mechanism of Met4 regulation by SCFMet30. The mechanism of Met4 activation by SCFMet30 is based on the prediction that the formation of Met4 homodimers antagonizes proper assembly between Met4 and cofactors (A), and that the dissociation of Met4 homodimers by SCFMet30 (B, step 1) is necessary to stabilize and/or rearrange the protein-protein interactions within the Met4/Met28/Cbf1 complex, triggering its proper assembly (B). The low abundance of SCFMet30 suggests that proteolysis of the remaining Met4 molecule occupying SCFMet30 (B, step 1) is necessary for SCFMet30 recycling (B, step 2). As a result, 'two stepping' with SCFMet30" could be necessary for each round of Met4 activity at a promoter (all steps involving SCFMet30 are marked in blue). The stabilizing effect of cofactors on the SCFMet30-Met4 interaction ('tight complex', note exposure of the UIM domain in Met4) allows Met4 inhibition by polyubiquitination only (C), unless methionine (D) or cysteine (DREP) is available to destabilize the tight interaction between Met4 and SCFMet30, allowing Met4 proteolysis. Disassembly of the Met4 complex by the proteasome could link activation of methionine biosynthesis to cell division by releasing the DNA binding cofactors Cbf1 and Met31/32 from promoters (D), which, at least in the case of Cbf1, would make it available for its cell division role. Dissociation of Met4 prior to its proteolysis could protect the cofactors and SCFMet30 from effects of the proteasome-mediated disassembly (DREP), preventing Cbf1 and/or Met31/32 release. See text for details.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: The emerging molecular mechanism of Met4 regulation by SCFMet30. The mechanism of Met4 activation by SCFMet30 is based on the prediction that the formation of Met4 homodimers antagonizes proper assembly between Met4 and cofactors (A), and that the dissociation of Met4 homodimers by SCFMet30 (B, step 1) is necessary to stabilize and/or rearrange the protein-protein interactions within the Met4/Met28/Cbf1 complex, triggering its proper assembly (B). The low abundance of SCFMet30 suggests that proteolysis of the remaining Met4 molecule occupying SCFMet30 (B, step 1) is necessary for SCFMet30 recycling (B, step 2). As a result, 'two stepping' with SCFMet30" could be necessary for each round of Met4 activity at a promoter (all steps involving SCFMet30 are marked in blue). The stabilizing effect of cofactors on the SCFMet30-Met4 interaction ('tight complex', note exposure of the UIM domain in Met4) allows Met4 inhibition by polyubiquitination only (C), unless methionine (D) or cysteine (DREP) is available to destabilize the tight interaction between Met4 and SCFMet30, allowing Met4 proteolysis. Disassembly of the Met4 complex by the proteasome could link activation of methionine biosynthesis to cell division by releasing the DNA binding cofactors Cbf1 and Met31/32 from promoters (D), which, at least in the case of Cbf1, would make it available for its cell division role. Dissociation of Met4 prior to its proteolysis could protect the cofactors and SCFMet30 from effects of the proteasome-mediated disassembly (DREP), preventing Cbf1 and/or Met31/32 release. See text for details.
Mentions: These observations have two implications for the mechanism by which SCFMet30 regulates Met4. First, the dissociation of Met4 homodimers by SCFMet30 could be necessary to stabilize and/or rearrange the protein-protein interactions within the Met4/Met28/Cbf1 complex and thereby trigger its full functional potential (Fig. 3B), explaining the positive regulatory role of SCFMet30. Indeed, Met4 dimerization represents an interesting conundrum, as it depends on the LZ domain also implicated in binding to the basic leucine zipper (bZIP) regulatory protein Met28 and the basic helix-loop-helix (bHLH) DNA binding protein Cbf1 (Fig. 2A, LZ). As such, Met4 dimerization could antagonize proper assembly and function of the Met4/Cbf1/Met28 complex.

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