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Pho4 bHLH Protein: Difference between revisions

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===PHOSPHATE SYSTEM POSITIVE REGULATORY PROTEIN PHO4/DNA COMPLEX===
===PHOSPHATE SYSTEM POSITIVE REGULATORY PROTEIN PHO4/DNA COMPLEX===


==Introduction==
== Introduction ==
 


The complete nucleotide sequence of Saccharomyces cerevisiae chromosome VI (270 kb) has revealed that it contains 129 predicted or known genes (300 bp or longer).(1)
The complete nucleotide sequence of Saccharomyces cerevisiae chromosome VI (270 kb) has revealed that it contains 129 predicted or known genes (300 bp or longer).(1)
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Binding of transcription factors to DNA is a key regulatory step in the control of gene expression. DNA sequences with high affinity for transcription factors occur more frequently in the genome than instances of genes bound or regulated by these factors. Although several mechanisms have been identified that influence the specificity of transcriptional regulation, it is not known if these can explain the observed genome-wide pattern of binding or regulation for a given transcription factor.(4)
Binding of transcription factors to DNA is a key regulatory step in the control of gene expression. DNA sequences with high affinity for transcription factors occur more frequently in the genome than instances of genes bound or regulated by these factors. Although several mechanisms have been identified that influence the specificity of transcriptional regulation, it is not known if these can explain the observed genome-wide pattern of binding or regulation for a given transcription factor.(4)
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PHO4 transcription factor is a basic helix loop helix structure with 312 amino acid residues with 4 functional domains commonly found in S. cerevisiae(6).  The amount of enviornmental inorganic phosphate regulates the activity of PHO4 binding (5).
PHO4 is a regulatory protein active during phosphorylation.  When phosphates are abundant PHO4 becomes phosphorylated by cyclin PHO80 and cyclin-dependent kinase PHO85, which causes PHO4 to become transported from nucleous to cytoplasm (5).
When there is limited amount of phosphate PHO4 is dephosphorylated and transported into the nucleous which activates the gene for transcription (5).  The particular genes at which PHO4 activaes are PHO5, PHO81 and PHO84(2). A cooperative interaction between transcription factor PHO2 and PHO4 typically occurs in order to activate the PHO5 gene(5).
Base flanking of PHO4 was compared to other bHLH structures such as MyoD, MAX, USF, E47 and CPF1(6). The binding angle degree of each structure may be a determining factor for specific dimer formation (6)
Other molecules such as nucleosomes and Cbf1 can cause PHO4 to not bind to promoter due to competition for the promoter site CACGTG (6). 
In the PHO5 gene,Due to PHO4 binding disrupting nucleosome binding structure this can cause chromatin reorganization of the PHO5 and murine mammary tumor virus(or mouse mammary tumor virus) promoters(7).  In order for MMTV to activate nucleosomes must be present, PHO4 can act as a way to inhibit the formation of nucleosome binding within this virus (7).
MMTV is a retrovirus which is transmitted by infected mother to offspring via breast milk due to extra choromsome (8).
The virus is typically integrated within the host DNA and is generally transported into the host via the gastrointestinal tract infecting the immune system(9).
Dendritic cells are the first infected cells in the MMTV virus which then are transmitted to other cell types(9).  When the virus infects dendritic cells they then become more mature and start migrating in response to chemokine macrophage inflammatory protein 3β(9).






{{ABSTRACT_PUBMED_9303313}}
{{ABSTRACT_PUBMED_9303313}}
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== Primary Sequence of Polypeptide ==
Pho4 contains DNA binding site is Chain C with Primary Sequence of DNA
(5’-CTCACACGTGGGACTAG-3’)
Primary Sequence of Polypeptide
'''MKRESHKHAEQARRNRLAVALHELASLIPAEWKQQNVSAAPSKATTVEAACRYIRHLQQNGST'''
'''1-MET-LYS-ARG-GLU-SER-HIS-LYS-HIS-ALA-GLU-GLN-ALA-ARG-ARG-ASN-ARG-LEU-ALA-VAL-ALA-LEU-HIS-GLU-LEU-ALA-SER-LEU-ILE-PRO-ALA-GLU-TRP-LYS-GLN-GLN-ASN-VAL-SER-ALA-ALA-PRO-SER-LYS-ALA-THR-THR-VAL-GLU-ALA-ALA-CYS-ARG-TYR-ILE-ARG-HIS-LEU-GLN-GLN-ASN-GLY-end
'''
[[Image:Pho4.jpg]]


==About this Structure==
==About this Structure==
[[1a0a]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A0A OCA].  
 
The crystal structure of a DNA-binding domain of PHO4 complexed has DNA resolution of 2.8 A. This domain folds into a basic-helix-loop-helix (bHLH) motif with a long loop. The compact loop contains a short alpha-helical segment. This helical segment places a tryptophan residue into an aromatic cluster forming the compact loop.A homodimer is formed when PHO4 binds to DNA this complex has the ability to direct reading of both the core E-box sequence CACGTG and its 3'-flanking bases. The Arg2 and His5 are both able to recognize the 3'-flanking bases GG. The residues involved in the E-box recognition are His5, Glu9 and Arg13, as already reported for bHLH/Zip proteins MAX and USF, and are different from those recognized by bHLH proteins MyoD and E47, although PHO4 is a bHLH protein.
 
[[1a0a]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A0A OCA].
 
 
'''Predicted functional partners of Pho4'''
•PH0 80
•PHO85
•PHO2
•PHO81
•MSN5
•PSE1
•SUA7
•SPT 15
•PHO4
•IN04
 
Sequence comparison to large number of mammalian and Drophilia BHLH proteins reveales similarity in the bHLH region.


==Reference==
==Reference==
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[[Category: Transcription factor]]
[[Category: Transcription factor]]
[[Category: Transcription-dna complex]]
[[Category: Transcription-dna complex]]
1. Murakami Y., Naitou M., Hagiwara H., Shibata T., Ozawa M., Sasanuma S., Sasanuma M., Tsuchiya Y., Soeda E., Yokoyama K., Yamazaki M., Tashiro H., Eki T."Analysis of the nucleotide sequence of chromosome VI from Saccharomyces cerevisiae." Nat. Genet. 10:261-268(1995) [PubMed: 7670463]
2. Legrain M., de Wilde M., Hilger F."Isolation, physical characterization and expression analysis of the Saccharomyces cerevisiae positive regulatory gene PHO4." Nucleic Acids Res. 14:3059-3073(1986) [PubMed: 3008105]
3. Ogawa Nobuo, Oshima Yasuji (May 1990). ‘’Functional Domains of a Positive Regulatory Protein, PHO4, for Transcriptional Control of the Phosphatase Regulon in Saccharomyces cerevisiae. Molecular and Cellular Biology. 10 (5): 2224-2236. PMC 360570. PMID 2183025.
4. Zhou Xu and O’Shea Erin K. (June 2011). ‘’ Integrated approaches reveal determinants of genome-wide binding and function of the transcription factor Pho4. Molecular Cell. 42 (6): 826-836. PMC 3127084. NIHM 305276.
5. Zhou X, O’Shea E (2011) Integrated approaches reveal determinants of genome-wide binding and function of the transcription factor PHO4. Mol Cell 42(6): 826-836
6. Shimizu T, Toumoto A et. al. (1997) Crystal Structure of PHO4 bHLH domain-DNA complex: flanking base recognition. The EMBO Journal 16(15): 4689-4697
7. Bergh F, Flinn E M. (2000) Comparision of Nucleosome Remodeling by Yeast Transcription Factor PHO4 and the Glucocorticoid Recptor. The Journal of Biological Chemistry 275(12): 9035-9042
8. Bittner, J. J. (1936). Some Possible Effects of Nursing on the Mammary Gland Tumor Incidence in Mice. Science 84 (2172): 162–162
9. Courreges C M, et. al. Critical Role of Dendritic Cells in Mouse Mammary Tumor Virus In Vivo Infection. Journal of Virology 81(8) 3769-3777

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Myron Williams, Michal Harel
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