MET4/YNL103W Summary Help

Standard Name MET4 1
Systematic Name YNL103W
Feature Type ORF, Verified
Description Leucine-zipper transcriptional activator; responsible for regulation of sulfur amino acid pathway; requires different combinations of auxiliary factors Cbf1p, Met28p, Met31p and Met32p; feedforward loop exists in the regulation of genes controlled by Met4p and Met32p; can be ubiquitinated by ubiquitin ligase SCF-Met30p, is either degraded or maintained in an inactive state; regulates degradation of its own DNA-binding cofactors by targeting them to SCF-Met30p (2, 3 and see Summary Paragraph)
Name Description METhionine requiring 1
Chromosomal Location
ChrXIV:427735 to 429753 | ORF Map | GBrowse
Gbrowse
Genetic position: -76 cM
Gene Ontology Annotations All MET4 GO evidence and references
  View Computational GO annotations for MET4
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulatory Role
Binding motifs Predicted MET4 Binding Site Locations
Resources
Mutant phenotypes All MET4 Phenotype evidence and references
Classical genetics
null
overexpression
Large-scale survey
null
overexpression
reduction of function
Resources
interactions All MET4 Interaction evidence and references
93 total interaction(s) for 40 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 7
  • Affinity Capture-RNA: 2
  • Affinity Capture-Western: 23
  • Biochemical Activity: 1
  • Reconstituted Complex: 8
  • Two-hybrid: 21
Genetic Interactions
  • Dosage Growth Defect: 3
  • Dosage Lethality: 3
  • Dosage Rescue: 2
  • Phenotypic Enhancement: 2
  • Phenotypic Suppression: 2
  • Synthetic Growth Defect: 4
  • Synthetic Lethality: 5
  • Synthetic Rescue: 10
Resources
Expression Summary
histogram
Resources
Protein Information All MET4 Protein evidence and references
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrXIV:427735 to 429753 | ORF Map | GBrowse
SGD ORF map
Genetic position: -76 cM
Last Update Coordinates: 2011-02-03 | Sequence: 2006-11-09
Subfeature details
Relative
Coordinates		 Chromosomal
Coordinates		 Most Recent Updates
Coordinates Sequence
CDS 1..2019 427735..429753 2011-02-03 2006-11-09
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000005047
SUMMARY PARAGRAPH for MET4

MET4 encodes a transcriptional activator that regulates the expression of genes involved in the biosynthesis of sulfur-containing amino acids, glutathione metabolism, heavy metal response, and the the sulfur-sparing response (4, 5, 6, 7). Met4p is a leucine zipper protein related to the family of the bZIP transcriptional activators (8, 9). Since Met4p lacks DNA binding activity, it regulates the transcription of its target genes by associating with DNA-binding cofactors, either Cbf1p or one of the two homologous proteins Met31p and Met32p (10, 8, 11, 12, 6). These DNA-binding cofactors localize Met4p to the promoters of its targets and the DNA-protein complex interaction is stabilized by the cofactor Met28p (10, 13). Once assembled onto promoters, Met4p is able to recruit other transcriptional coactivator complexes such as Mediator and SAGA (14).

Expression of Met4p is regulated both transcriptionally, via the general amino acid control transcription factor Gcn4p (15), and post-translationally via control of degradation; the latter appears to be the major mechanism of regulation. Various conditions, such as sulfur source and availability, oxidative stress, exposure to heavy metals, and elevated levels of intracellular cysteine, methionine, or AdoMet, result in changes in Met4p protein levels through the action of the ubiquitin ligase complex SCF(Met30) (16, 17, 18, 19, 20, 21, 22, 23). Met4p is regulated positively and negatively by SCF(Met30) by both proteolysis-dependent and -independent means (24, 17, 25, 20, and reviewed in 26 and 19). SCF(Met30) modification of Met4p does signal the transcription factor for eventual 26S proteasomal degradation but prevention of proteasomal recognition, either through continued and tight association with SCF(Met30) or by the action of a ubiquitin-interacting motif within Met4p, can stabilize the polyubiquitinated form of the protein and prevent it from being degraded (27, 28, 24, and reviewed in 19). Null mutants for met4 are methionine, homocysteine, and AdoMet auxotrophs and overexpression of MET4 results in lethality (15, 4, 29).

Last updated: 2011-02-07

References cited on this page View Complete Literature Guide for MET4
1) Masselot M and De Robichon-Szulmajster H  (1975) Methionine biosynthesis in Saccharomyces cerevisiae. I. Genetical analysis of auxotrophic mutants. Mol Gen Genet 139(2):121-32
2) Blaiseau PL and Thomas D  (1998) Multiple transcriptional activation complexes tether the yeast activator Met4 to DNA. EMBO J 17(21):6327-36
3) McIsaac RS, et al.  (2012) Perturbation-based analysis and modeling of combinatorial regulation in the yeast sulfur assimilation pathway. Mol Biol Cell 23(15):2993-3007
4) Thomas D and Surdin-Kerjan Y  (1997) Metabolism of sulfur amino acids in Saccharomyces cerevisiae. Microbiol Mol Biol Rev 61(4):503-32
5) Wheeler GL, et al.  (2003) Coupling of the transcriptional regulation of glutathione biosynthesis to the availability of glutathione and methionine via the Met4 and Yap1 transcription factors. J Biol Chem 278(50):49920-8
6) Lee TA, et al.  (2010) Dissection of combinatorial control by the met4 transcriptional complex. Mol Biol Cell 21(3):456-69
7) Fauchon M, et al.  (2002) Sulfur sparing in the yeast proteome in response to sulfur demand. Mol Cell 9(4):713-23
8) Thomas D, et al.  (1992) MET4, a leucine zipper protein, and centromere-binding factor 1 are both required for transcriptional activation of sulfur metabolism in Saccharomyces cerevisiae. Mol Cell Biol 12(4):1719-27
9) Thomas D, et al.  (1990) Gene-enzyme relationship in the sulfate assimilation pathway of Saccharomyces cerevisiae. Study of the 3'-phosphoadenylylsulfate reductase structural gene. J Biol Chem 265(26):15518-24
10) Kuras L, et al.  (1997) Assembly of a bZIP-bHLH transcription activation complex: formation of the yeast Cbf1-Met4-Met28 complex is regulated through Met28 stimulation of Cbf1 DNA binding. EMBO J 16(9):2441-51
11) Blaiseau PL, et al.  (1997) Met31p and Met32p, two related zinc finger proteins, are involved in transcriptional regulation of yeast sulfur amino acid metabolism. Mol Cell Biol 17(7):3640-8
12) Su NY, et al.  (2008) A Dominant Suppressor Mutation of the met30 Cell Cycle Defect Suggests Regulation of the Saccharomyces cerevisiae Met4-Cbf1 Transcription Complex by Met32. J Biol Chem 283(17):11615-24
13) Kuras L, et al.  (1996) A heteromeric complex containing the centromere binding factor 1 and two basic leucine zipper factors, Met4 and Met28, mediates the transcription activation of yeast sulfur metabolism. EMBO J 15(10):2519-29
14) Leroy C, et al.  (2006) Independent recruitment of mediator and SAGA by the activator Met4. Mol Cell Biol 26(8):3149-63
15) Mountain HA, et al.  (1993) The general amino acid control regulates MET4, which encodes a methionine-pathway-specific transcriptional activator of Saccharomyces cerevisiae. Mol Microbiol 7(2):215-28
16) Lafaye A, et al.  (2005) Combined proteome and metabolite-profiling analyses reveal surprising insights into yeast sulfur metabolism. J Biol Chem 280(26):24723-30
17) Yen JL, et al.  (2005) The yeast ubiquitin ligase SCFMet30 regulates heavy metal response. Mol Biol Cell 16(4):1872-82
18) Barbey R, et al.  (2005) Inducible dissociation of SCF(Met30) ubiquitin ligase mediates a rapid transcriptional response to cadmium. EMBO J 24(3):521-32
19) Chandrasekaran S and Skowyra D  (2008) The emerging regulatory potential of SCFMet30 -mediated polyubiquitination and proteolysis of the Met4 transcriptional activator. Cell Div 3:11
20) Kuras L, et al.  (2002) Dual regulation of the met4 transcription factor by ubiquitin-dependent degradation and inhibition of promoter recruitment. Mol Cell 10(1):69-80
21) Menant A, et al.  (2006) Determinants of the ubiquitin-mediated degradation of the Met4 transcription factor. J Biol Chem 281(17):11744-54
22) Rouillon A, et al.  (2000) Feedback-regulated degradation of the transcriptional activator Met4 is triggered by the SCF(Met30 )complex. EMBO J 19(2):282-94
23) Kuras L and Thomas D  (1995) Functional analysis of Met4, a yeast transcriptional activator responsive to S-adenosylmethionine. Mol Cell Biol 15(1):208-16
24) Flick K, et al.  (2006) A ubiquitin-interacting motif protects polyubiquitinated Met4 from degradation by the 26S proteasome. Nat Cell Biol 8(5):509-15
25) Flick K, et al.  (2004) Proteolysis-independent regulation of the transcription factor Met4 by a single Lys 48-linked ubiquitin chain. Nat Cell Biol 6(7):634-41
26) Kaiser P, et al.  (2006) The yeast ubiquitin ligase SCFMet30: connecting environmental and intracellular conditions to cell division. Cell Div 1:16
27) Thomas D, et al.  (1995) Met30p, a yeast transcriptional inhibitor that responds to S-adenosylmethionine, is an essential protein with WD40 repeats. Mol Cell Biol 15(12):6526-34
28) Chandrasekaran S, et al.  (2006) Destabilization of binding to cofactors and SCFMet30 is the rate-limiting regulatory step in degradation of polyubiquitinated Met4. Mol Cell 24(5):689-99
29) Patton EE, et al.  (2000) SCF(Met30)-mediated control of the transcriptional activator Met4 is required for the G(1)-S transition. EMBO J 19(7):1613-24
30) Harbison CT, et al.  (2004) Transcriptional regulatory code of a eukaryotic genome. Nature 431(7004):99-104