title: Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2.
abstract: Transcriptional regulation of ergosterol biosynthesis in fungi is crucial for sterol homeostasis and for resistance to azole drugs. In Saccharomyces cerevisiae, the Upc2 transcription factor activates the expression of related genes in response to sterol depletion by poorly understood mechanisms. We have determined the structure of the C-terminal domain (CTD) of Upc2, which displays a novel α-helical fold with a deep hydrophobic pocket. We discovered that the conserved CTD is a ligand-binding domain and senses the ergosterol level in the cell. Ergosterol binding represses its transcription activity, while dissociation of the ligand leads to relocalization of Upc2 from cytosol to nucleus for transcriptional activation. The C-terminal activation loop is essential for ligand binding and for transcriptional regulation. Our findings highlight that Upc2 represents a novel class of fungal zinc cluster transcription factors, which can serve as a target for the developments of antifungal therapeutics.
authors: College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea.
authors: Huiseon
authors: H
authors: Yang
authors: College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea.
authors: Junsen
authors: J
authors: Tong
authors: Department of Chemistry, Chonnam National University, Gwangju 500-757, South Korea.
authors: Chul Won
authors: CW
authors: Lee
authors: College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea.
authors: Subin
authors: S
authors: Ha
authors: School of Life Science, Steitz Center for Structural Biology, and Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors: Soo Hyun
authors: SH
authors: Eom
authors: College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea.
authors: Young Jun
authors: YJ
authors: Im
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D001665:Binding Sites; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000187:drug effects; D004875:Ergosterol / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008024:Ligands; D013058:Mass Spectrometry; D008954:Models, Biological; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012015:Reference Standards; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D000935:Antifungal Agents; D008024:Ligands; D050505:Mutant Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; C113958:UPC2 protein, S cerevisiae; C010905:dehydroergosterol; D049452:Green Fluorescent Proteins; D015725:Fluconazole; D004875:Ergosterol