Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wroclaw University of Science and Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland.
Department of Molecular Medicine, USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Int J Mol Sci. 2021 Mar 11;22(6):2868. doi: 10.3390/ijms22062868.
The basic helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, ranging from differentiation and development control by oxygen and toxins sensing to circadian clock setting. In addition to the well-preserved DNA-binding bHLH and PAS domains, bHLH-PAS proteins contain long intrinsically disordered C-terminal regions, responsible for regulation of their activity. Our aim was to analyze the potential connection between disordered regions of the bHLH-PAS transcription factors, post-transcriptional modifications and liquid-liquid phase separation, in the context of disease-associated missense mutations. Highly flexible disordered regions, enriched in short motives which are more ordered, are responsible for a wide spectrum of interactions with transcriptional co-regulators. Based on our in silico analysis and taking into account the fact that the functions of transcription factors can be modulated by posttranslational modifications and spontaneous phase separation, we assume that the locations of missense mutations inducing disease states are clearly related to sequences directly undergoing these processes or to sequences responsible for their regulation.
基本螺旋-环-螺旋/芳香烃受体核转录因子（bHLH-PAS）蛋白家族是一类转录因子，调节参与多种功能的广泛基因的表达，从分化和发育控制到氧和毒素感应以及生物钟设置。除了保存完好的 DNA 结合 bHLH 和 PAS 结构域外，bHLH-PAS 蛋白还含有长的内在无序的 C 端区域，负责调节其活性。我们的目的是分析疾病相关错义突变背景下，bHLH-PAS 转录因子的无序区域、转录后修饰和液-液相分离之间的潜在联系。富含短基序的高度灵活无序区域更有序，负责与转录共调节剂的广泛相互作用。基于我们的计算机分析，并考虑到转录因子的功能可以通过翻译后修饰和自发相分离来调节，我们假设导致疾病状态的错义突变的位置与直接经历这些过程的序列或负责其调节的序列明显相关。
