College of Pharmacy, Chonnam National University, Gwangju 500-757, South Korea.
Department of Chemistry, Chonnam National University, Gwangju 500-757, South Korea.
Nat Commun. 2015 Feb 6;6:6129. doi: 10.1038/ncomms7129.
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.
真菌中麦角固醇生物合成的转录调控对于甾醇动态平衡和唑类药物抗性至关重要。在酿酒酵母中，Upc2 转录因子通过未知的机制响应固醇耗竭，激活相关基因的表达。我们已经确定了 Upc2 的 C 端结构域（CTD）的结构，该结构域显示出一种新颖的α螺旋折叠，具有深的疏水性口袋。我们发现保守的 CTD 是一个配体结合域，能够感知细胞内的麦角固醇水平。麦角固醇结合抑制其转录活性，而配体的解离导致 Upc2 从细胞质重新定位到细胞核，从而进行转录激活。C 端激活环对于配体结合和转录调控至关重要。我们的研究结果表明，Upc2 代表了一类新型的真菌锌簇转录因子，可作为开发抗真菌治疗药物的靶点。
