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The Gal4 transcription factor is a positive regulator of gene expression of galactose-induced genes [1]. The Gal4 protein represents a large fungal family of transcription factors, Gal4 family, which includes Saccharomyces cerevisiae e.g. Oaf1, Pip2, Pdr1, Pdr3, Leu3 [2].

Gal4 domains

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The transcription factor Gal4 include two executive domains, DNA binding and activation domains, which provide strong gene activation after galactose induction.

Gal4 domains and regulation

DNA binding domain

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The N-terminal DNA binding domain belongs to the Zn(2)-C6 fungal family, which forms a Zn – cysteines thiolate cluster [3][4] The Gal4 DNA Binding domain recognized specifically response element in GAL1 promoter [5][6].

Gal4 activation domain

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The C-terminal activation domain belongs to the nine amino acids TransActivation Domain family, 9aaTAD, together with Oaf1, Pip2, Pdr1, Pdr3, but also p53, E2A, MLL [7][8][9][10][11]

Regulation

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Galactose induces Gal4 mediated transcription albeit Glucose causes severe repression [12][13]. As a part of the Gal4 regulation, inhibitory protein Gal80 recognizes and binds to the Gal4 region (853-874 aa) [14][15][16] including activation domain 9aaTAD [17][18][19]. The inhibitory protein Gal80 is sequestered by regulatory protein Gal3 in Galactose dependent manner [20][21][22][23].

Mutants

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The Gal4 loss-of-function mutant gal4-64 (1-852 aa, deletion of the Gal4 C-terminal 29 aa) lost both interaction with Gal80 and activation function [24][25][26].

In the Gal4 reverted mutant Gal4C-62 mutant [27], a sequence (QTAY N AFMN) with the 9aaTAD pattern emerged and restored activation function of the Gal4 protein [28].

Inactive constructs

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The activation domain Gal4 is inhibited by C-terminal domain in some Gal4 constructs [29] [30] [31].

Proteosome

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A subunit of the 26 S proteasome Sug2 regulatory protein has a molecular and functional interaction with Gal4 function [32][33]. Proteolytic turnover of the Gal4 transcription factor is not required for function in vivo [34]. The native Gal4 monoubiquitination protects from 19S-mediated destabilizing under inducing conditions [35].

Mediators of transcription

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The Gal4 activation function is mediated by MED15 (Gal11) [36][37][38][39][40][41][42][43].

The Gal4 protein interacts also with other mediators of transcription as are Tra1, [44][45][46][47][48] TAF9, [49] and SAGA/MED15 complex [50][51].

Application

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The broad use of the Gal4 is in yeast two hybrid system to screen or to assay protein-protein interactions in eukaryotic cells from yeast to human.

In the GAL4/UAS system, the Gal4 protein and Gal4 upstream activating region (UAS) are used to study the gene expression and function in organisms such as the fruit fly.

The Gal4 and inhibitory protein Gal80 have found application in a genetics technique for creating individually labeled homozygous cells called Mosaic analysis with a repressible cell marker MARCM.

References

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  1. ^ Klar AJ, Halvorson HO (1974). "Studies on the positive regulatory gene, GAL4, in regulation of galactose catabolic enzymes in Saccharomyces cerevisiae". Mol. Gen. Genet. 135 (3): 203–12. PMID 4376212.
  2. ^ Schjerling P, Holmberg S (1996). "Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators". Nucleic Acids Res. 24 (23): 4599–607. PMC 146297. PMID 8967907.
  3. ^ Marmorstein R, Carey M, Ptashne M, Harrison SC (1992). "DNA recognition by GAL4: structure of a protein-DNA complex". Nature. 356 (6368): 408–14. Bibcode:1992Natur.356..408M. doi:10.1038/356408a0. PMID 1557122.
  4. ^ Pan T, Coleman JE (1990). "The DNA binding domain of GAL4 forms a binuclear metal ion complex". Biochemistry. 29 (12): 2023–9. PMID 2186803.
  5. ^ Liam, Keegan; G., Gill; M., Ptashne (February 1986). "Separation of DNA binding from the transcription-activating function of a eukaryotic regulatory protein". Science. 231, (4739). doi:10.1126/science.3080805.{{cite journal}}: CS1 maint: extra punctuation (link)
  6. ^ Edward, Giniger; Susan M.Varnum, Varnum; Mark, Ptashne (April 1985). "Specific DNA binding of GAL4, a positive regulatory protein of yeast". Cell. 40 (4). doi:10.1016/0092-8674(85)90336-8.
  7. ^ Ding WV, Johnston SA (1997). "The DNA binding and activation domains of Gal4p are sufficient for conveying its regulatory signals". Mol. Cell. Biol. 17 (5): 2538–49. PMC 232103. PMID 9111323.
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  9. ^ Piskacek S, Gregor M, Nemethova M, Grabner M, Kovarik P, Piskacek M (2007). "Nine-amino-acid transactivation domain: establishment and prediction utilities". Genomics. 89 (6): 756–68. doi:10.1016/j.ygeno.2007.02.003. PMID 17467953.
  10. ^ Piskacek M, Havelka M, Rezacova M, Knight A (2016). "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLoS ONE. 11 (9): e0162842. Bibcode:2016PLoSO..1162842P. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ Piskacek M, Havelka M, Rezacova M, Knight A (2017). "The 9aaTAD Is Exclusive Activation Domain in Gal4". PLoS ONE. 12 (1): e0169261. Bibcode:2017PLoSO..1269261P. doi:10.1371/journal.pone.0169261. PMC 5215927. PMID 28056036.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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  13. ^ Griggs DW, Johnston M (1991). "Regulated expression of the GAL4 activator gene in yeast provides a sensitive genetic switch for glucose repression". Proc. Natl. Acad. Sci. U.S.A. 88 (19): 8597–601. Bibcode:1991PNAS...88.8597G. PMC 52556. PMID 1924319.
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  17. ^ Piskacek S, Gregor M, Nemethova M, Grabner M, Kovarik P, Piskacek M (2007). "Nine-amino-acid transactivation domain: establishment and prediction utilities". Genomics. 89 (6): 756–68. doi:10.1016/j.ygeno.2007.02.003. PMID 17467953.
  18. ^ Piskacek M, Havelka M, Rezacova M, Knight A (2016). "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLoS ONE. 11 (9): e0162842. Bibcode:2016PLoSO..1162842P. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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Category:Transcription coregulators Category:Galactose Category:Nutrition Category:Sugar substitutes Category:Fungal models Category:Digestive system Category:Probiotics Category:Osmophiles Category:Yeasts used in brewing Category:Leavening agents Category:Oenology Category:Edible fungi

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