Biology:Pdr1p

From HandWiki
PDR1p Physical Details.png
A Diagram of Pdr1p transcription. A Pdr1p dimer binds to PDRE and recruits transcriptional machineries necessary for transcription.

Pdr1p (Pleiotropic Drug Resistance 1p) is a transcription factor found inyeast and is a key regulator of genes involved in general drug response. It induces the expression of ATP-binding cassette transporter, which can export toxic substances out of the cell, allowing cells to survive under general toxic chemicals. [1][2][3][4][5] It binds to DNA sequences that contain certain motifs called pleiotropic drug response element (PDRE).[1] Pdr1p is encoded by a gene called PDR1 (also known as YGL013C) on chromosome VII.[2][6]

Transcriptional role

Motif Analysis of PDRE

Pdr1p is a main regulator of PDR genes and is known to target about 50 genes.[1][7] Pdr1p binds to sequence 5'-TCCGYGGR-3' of PDRE, which is located within the promoter sequences of its target genes.[8][9] 218 genes are reported to possess PDRE.[10] Pdr1p is observed to bind PDRE sites on DNA at basal level and also after simulation with toxins. This shows that Pdr1p-DNA interaction isn't dependent on toxic stimulation. This also suggests an involvement of activator(s) or co-activator(s) that induce PDR genes along with Pdr1p.[1] Pdr1p has a functional homolog called Pdr3p encoded by gene called PDR3. Pdr3p is known to be regulated by Pdr3p and Pdr1p.[11] Pdr1p can form a homodimer with itself or heterodimer with Pdr3p. [12][5]

Loss of function studies of both PDR1 and PDR3 revealed that Pdr1p mutant shows lower tolerance (grows less in culture) against organic toxins such as cycloheximide and oligomycin. This confirms the functions of Prf1p that confer stronger drug response phenotype than Pdr3p. However, Pdr3p is crucial for PDR responses since cells containing loss of function mutation in both PDR1 and PDR3 genes weren't able to grow at all in the presence of those two toxins.[9]

Both Pdr1p and Pdr3p regulate Pdr5p, which is an ATP-binding cassette transporter.[9] A single amino acid substitution mutation, which is a gain of function mutation of Pdr1p denoted as pdr1-3 (F815S, substitution mutation of Phenylalanine at 815th of the polypeptide by Serine) leads to an over-expression of mRNA of PDR5, which codes for Pdr5p.[13] For cells treated with fluphenazine, Pdr1p was the only transcription factor necessary for PDR response genes induction. But at basal level, Pdr1p can be partially compensated by Pdr3p, a functional homolog of Pdr1p.[1]

Structure

Protein structure of Pdr1p, having two main domains in N- and C-terminus ends.

Pdr1p and Pdr3p is a part of Gal4 transcription factor family due to their zinc-finger DNA binding motif, which is located in N-terminus end of Pdr1p. Pdr1p also contains a long internal region of many inhibitory domains and possess a C-terminal transcription activation domain (amino acids 879–1036). The transcriptional activation domain is rich in glutamine and asparagine, which is theorized to facilitate in protein-protein interaction via hydrogen bonding.[11][10] A study found that DNA-binding domain of Pdr1p was sufficient for recognizing its endogenous target genes. [14] Strong drug resistance phenotype of yeasts with pdr1-3 is speculated due to its inability to bind to ligands that otherwise cause conformational change to inhibit the transcriptional activity of Pdr1p.[10]

Interaction with other transcription factors

Pdr1p and Pdr3p also interact with other transcription factors and their associated networks such as Yap1p, which controls oxidative stress response, and Rpn4p, which regulates proteasome activities, depending on the kinds of toxins cells face.[8] It is known that Pdr1p induces the expression of Rpn4p.[10]

Importance

Drugs or toxic chemicals are useful in killing pathogenic bacteria or tumor cells, and studying how they mechanistically develop tolerance to a wide range of drugs can improve anti-bacterial and cancer therapeutics.[12] Pdr5p has a similar mechanism of actions and functions to human multidrug resistance protein, whose overexpression is shown to provide chemical tolerance to cancer cells. Studying Pdr5p and how it is regulated by Pdr1p in yeast can give insights into how multi drug resistance occurs in mammals.[15]

By using pdr1-3 and fusing the promoter of Pdr5p to genes that code for membrane proteins of interests, yeast membrane proteins such as Pdr5p, Yor1, and Drs2 can be expressed highly so that they can be efficiently cloned and purified for further studies.[16]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "The central role of PDR1 in the foundation of yeast drug resistance". The Journal of Biological Chemistry 282 (7): 5063–74. February 2007. doi:10.1074/jbc.M610197200. PMID 17158869. 
  2. ↑ 2.0 2.1 "Gene: PDR1 (YGL013C) - Summary - Saccharomyces cerevisiae - Ensembl genome browser 92" (in en-gb). http://uswest.ensembl.org/Saccharomyces_cerevisiae/Gene/Summary?g=YGL013C;r=VII:469092-472298;t=YGL013C. 
  3. ↑ "The multidrug resistance gene PDR1 from Saccharomyces cerevisiae". The Journal of Biological Chemistry 262 (35): 16871–9. December 1987. doi:10.1016/S0021-9258(18)45464-6. PMID 3316228. 
  4. ↑ "Pleiotropic drug-resistance attenuated genomic library improves elucidation of drug mechanisms". Molecular BioSystems 11 (11): 3129–36. November 2015. doi:10.1039/c5mb00406c. PMID 26381459. 
  5. ↑ 5.0 5.1 "The yeast zinc finger regulators Pdr1p and Pdr3p control pleiotropic drug resistance (PDR) as homo- and heterodimers in vivo". Molecular Microbiology 46 (5): 1429–40. December 2002. doi:10.1046/j.1365-2958.2002.03262.x. PMID 12453227. 
  6. ↑ "PDR1 Sequence | SGD". https://www.yeastgenome.org/locus/S000002981/sequence. 
  7. ↑ "Genetic reconstruction of a functional transcriptional regulatory network" (in En). Nature Genetics 39 (5): 683–7. May 2007. doi:10.1038/ng2012. PMID 17417638. 
  8. ↑ 8.0 8.1 "Structure and properties of transcriptional networks driving selenite stress response in yeasts". BMC Genomics 9: 333. July 2008. doi:10.1186/1471-2164-9-333. PMID 18627600. 
  9. ↑ 9.0 9.1 9.2 "Transcriptional control of the yeast PDR5 gene by the PDR3 gene product". Molecular and Cellular Biology 14 (7): 4653–61. July 1994. doi:10.1128/MCB.14.7.4653. PMID 8007969. 
  10. ↑ 10.0 10.1 10.2 10.3 "Functional dissection of Pdr1p, a regulator of multidrug resistance in Saccharomyces cerevisiae". Molecular Genetics and Genomics 267 (1): 96–106. March 2002. doi:10.1007/s00438-002-0642-0. PMID 11919720. 
  11. ↑ 11.0 11.1 "Yeast multidrug resistance: the PDR network". Journal of Bioenergetics and Biomembranes 27 (1): 71–6. February 1995. doi:10.1007/BF02110333. PMID 7629054. 
  12. ↑ 12.0 12.1 "Complex interplay among regulators of drug resistance genes in Saccharomyces cerevisiae". The Journal of Biological Chemistry 279 (27): 27855–60. July 2004. doi:10.1074/jbc.M403487200. PMID 15123673. 
  13. ↑ "Molecular and phenotypic characterization of yeast PDR1 mutants that show hyperactive transcription of various ABC multidrug transporter genes". Molecular & General Genetics 256 (4): 406–15. October 1997. doi:10.1007/s004380050584. PMID 9393438. 
  14. ↑ "An artificial transcription activator mimics the genome-wide properties of the yeast Pdr1 transcription factor". EMBO Reports 2 (6): 493–8. June 2001. doi:10.1093/embo-reports/kve114. PMID 11415981. 
  15. ↑ "PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1". The Journal of Biological Chemistry 269 (3): 2206–14. January 1994. doi:10.1016/S0021-9258(17)42155-7. PMID 8294477. 
  16. ↑ "New examples of membrane protein expression and purification using the yeast based Pdr1-3 expression strategy". Journal of Biotechnology 191: 158–64. December 2014. doi:10.1016/j.jbiotec.2014.07.010. PMID 25036752. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Pdr1p&oldid=3645543"