Abstract
The bHLH-PAS (basic helix-loop-helix/ Period-ARNT-Single minded) proteins are a family of transcriptional regulators commonly occurring in living organisms. bHLH-PAS members act as intracellular and extracellular “signals” sensors, initiating response to endo- and exogenous signals, including toxins, redox potential, and light. The activity of these proteins as transcription factors depends on nucleocytoplasmic shuttling: the signal received in the cytoplasm has to be transduced, via translocation, to the nucleus. It leads to the activation of transcription of particular genes and determines the cell response to different stimuli. In this review, we aim to present the current state of knowledge concerning signals that affect shuttling of bHLH-PAS transcription factors. We summarize experimentally verified and published nuclear localization signals/nuclear export signals (NLSs/NESs) in the context of performed in silico predictions. We have used most of the available NLS/NES predictors. Importantly, all our results confirm the existence of a complex system responsible for protein localization regulation that involves many localization signals, which activity has to be precisely controlled. We conclude that the current stage of knowledge in this area is still not complete and for most of bHLH-PAS proteins an experimental verification of the activity of further NLS/NES is needed.
Highlights
The bHLH-PAS proteins are a family of transcriptional regulators commonly occurring in living organisms [1,2]
We have studied human representatives of bHLH/PAS class I: AHR (Aryl hydrocarbon Receptor), hypoxia inducible factor 1α (HIF-1α) (Hypoxia Inducible Factor), HIF-2α and HIF-3α, SIM1 (Single-minded homolog) and SIM2, NPAS1-4 (Neuronal PAS domain-containing protein), CLOCK, and representatives of class II: ARNT (Aryl Hydrocarbon Nuclear Translocator), ARNT2, ARNTL1
In the case of many transcription factors presented in this review, at least one of nuclear localization signal (NLS)/nuclear export signal (NES) motifs is located in the C-terminal region (Figure 3) [19,20,21,48,52,55,76] responsible for interaction with activators/repressors influencing protein activity
Summary
The bHLH-PAS (basic helix-loop-helix/ Period-ARNT-Single minded) proteins are a family of transcriptional regulators commonly occurring in living organisms [1,2]. BHLH-PAS proteins, like many other transcription factors (TFs), dimerize with other family members to create functional heterodimer acting as a functional complex regulating the expression of genes under its control [4]. BHLH-PAS proteins are an important class of TFs which activity depends on nucleocytoplasmic shuttling To perform their function as sensors, indispensable is receiving the signal in cytoplasm and its transduction, by translocation, to the nucleus. It leads to the activation of particular genes transcription. Regulation of the Subcellular Localization of Class I bHLH-PAS Transcription Factors
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