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

Abstract

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.

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…Missense mutations associated with diseases are found mostly within IDRs [ 577 ]. These mutations in IDRs can cause the dysregulation of LLPS by changing the threshold concentration for condensate formation [ 578 , 579 , 580 ], modulating the exposure of the aggregation-prone regions [ 577 ], and interfering with RNA interactions [ 27 ].…”

“…Missense mutations associated with diseases are found mostly within IDRs [ 577 ]. These mutations in IDRs can cause the dysregulation of LLPS by changing the threshold concentration for condensate formation [ 578 , 579 , 580 ], modulating the exposure of the aggregation-prone regions [ 577 ], and interfering with RNA interactions [ 27 ]. IDR mutations are capable of disrupting phase separation in important cellular processes, turning dynamic liquid droplets into aberrant fibril aggregates [ 581 , 582 , 583 ] to cause mislocalization or the gain/loss of functions [ 27 , 584 ].…”