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User:CellBio123567/Pho4

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General definition and Purpose of Pho4

Pho4 is a protein with a basic helix-loop-helix (bHLH) structure. The Pho4 protein is found in S. cerevisiae and other yeasts.[1] It functions as a transcription factor to regulate phosphate responsive genes located in yeast cells.[2] Pho4 is able to to locate and bind to phosphate responsive genes by binding to DNA sequences containing the bHLH binding site 5'-CACGTG-3'.[3]

Structure of Pho4

This is a crystallographic structure of the Pho4 protein/DNA complex that is found in yeast cells that was created using PyMol based on the PDB protein databank.[4] This structure was created by fellow Wiki user Boghog.[4]

Helical regions are represented by ribbons; non-regular secondary structure elements by thin tubes. Molecules A and B are colored cyan and lime-green, respectively. Helical structure is clearly seen in the loop region.[2] The PHO4 protein consists of 312 amino acid residues and has four functional domains.[5] PHO4 is one of the regulatory proteins indispensable for transcription of the PHO5, PHO81 and PHO84 genes.[5] The DNA-binding domain of PHO4 consists of two helices, designated H1 and H2, separated by a long loop that contains a novel α-helical region. PHO4 binds to DNA as a homodimer and the two monomers fold into a parallel, left-handed four-helix bundle.[5] PHO4 protein lacks an inner hydrogen network.[5]

Mechanism of Pho4

Pho4 is a transcription factor that assists in regulating cell growth.[6] When activated, Pho4 is translocated to the nucleus. Pho4 has a Nuclear Exchange factor that an importin protein is able to bind to. The importin protein will bind to its "signal" or nuclear exchange factor and aid in translocating the nuclear exchange factor tagged protein into the nucleus. Additionally, another transcription factor known as Pho2, binds to Pho4 and assists in Pho4’s ability to bind tightly to its binding site on its specific target genes.[6] This completes the addition of the binding partners that Pho4 needs in order to be capable of acting as a transcription factor by up-regulating the transcription of phosphate-responsive genes.

Regulation of Pho4

Suppression

Down regulation of the transcription factor Pho4 is seen when the yeast cell has a phosphate rich environment. Under high phosphate concentrations, it is seen that a cyclin-dependent kinase, known as PHO80-PHO50, phosphorylates PHO4 on its serine residues (O’Neil et. al 209-212).[7] This blocks the binding sites for the importin and Pho2 transcription factor and allows for the receptor Msn5p to assist in the removal of the Pho4 protein from the nucleus and back into the cytoplasmic space.[8] Additionally, because the binding site of importin on the Pho4 protein is blocked from the phosphorylation that PHO4 undergoes, PHO4 is no longer able to be translocated into the nucleus.

Up-regulation

Up-regulation of Pho4 is seen in phosphate deficient yeast cells. This occurs due to cyclin dependent kinase PHO80-PHO85 being inhibited by the cyclin dependent inhibitor PHO81.[7] In low concentrations of phosphate the CDK inhibitor PHO80-PHO85 is able to inhibit PHO80-PHO85 from phosphorylating PHO4 at its serine residues.[7] When this occurs, importin and PHO2 are able to bind to PHO4 and assist in the translocation and tight binding to its binding site on the gene PHO5 which will then become up-regulated.[7]

  1. ^ Berben, Gilbert; Legrain, Michèle; Gilliquet, Véronique; Hilger, François (1990-09-XX). "The yeast regulatory genePHO4 encodes a helix-loop-helix motif". Yeast. 6 (5): 451–454. doi:10.1002/yea.320060510. ISSN 0749-503X. {{cite journal}}: Check date values in: |date= (help)
  2. ^ a b Shimizu, T. (1997-08-01). "Crystal structure of PHO4 bHLH domain-DNA complex: flanking base recognition". The EMBO Journal. 16 (15): 4689–4697. doi:10.1093/emboj/16.15.4689.
  3. ^ Shao, D (1998-02-01). "A cysteine residue in helixII of the bHLH domain is essential for homodimerization of the yeast transcription factor Pho4p". Nucleic Acids Research. 26 (3): 710–714. doi:10.1093/nar/26.3.710.
  4. ^ a b Boghog2 (2009-01-03), English: Crystallographic structure of the yeast Pho4/DNA complex based on PDB: 1a0a​ coordinates., retrieved 2021-05-10 {{citation}}: zero width space character in |title= at position 86 (help)CS1 maint: numeric names: authors list (link)
  5. ^ a b c d Ogawa, N; Oshima, Y (1990-05-XX). "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. doi:10.1128/mcb.10.5.2224. ISSN 0270-7306. {{cite journal}}: Check date values in: |date= (help)
  6. ^ a b Lim, W; Mayer; Pawson (2015). Cell Signaling: Principles and Mechanisms. New York, New york: Garland Science. pp. 119–120.
  7. ^ a b c d O'Neill, E. M.; Kaffman, A.; Jolly, E. R.; O'Shea, E. K. (1996-01-12). "Regulation of PHO4 Nuclear Localization by the PHO80-PHO85 Cyclin-CDK Complex". Science. 271 (5246): 209–212. doi:10.1126/science.271.5246.209. ISSN 0036-8075.
  8. ^ "PHO4 | SGD". www.yeastgenome.org. Retrieved 2021-05-10.
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