The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development

Abstract

The bHLH-PAS proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, 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 their activity regulation. Our aim was to analyse the potential connection between disordered regions of the bHLH-PAS transcription factors with posttranscriptional modifications and liquid-liquid phase separation in the context of the disease-associated missense mutations. Highly flexible disordered regions, enriched in short more ordered motives, are responsible for wide spectrum of interactions with transcriptional co-regulators. Based on our in silico analysis and taking into account fact that transcription factors functions can be modulated by posttranslational modifications and spontaneous phase separation, we assume that the location of missense mutations inducing disease states, is clearly related to sequences directly undergoing these processes or to sequences responsible for their activity regulation.