The evolution and structure/function of bHLH-PAS transcription factor family

Abstract

Proteins that contain basic helix-loop-helix (bHLH) and Per-Arnt-Sim motifs (PAS) function as transcription factors. bHLH-PAS proteins exhibit essential and diverse functions throughout the body, from cell specification and differentiation in embryonic development to the proper function of organs like the brain and liver in adulthood. bHLH-PAS proteins are divided into two classes, which form heterodimers to regulate transcription. Class I bHLH-PAS proteins are typically activated in response to specific stimuli, while class II proteins are expressed more ubiquitously. Here, we discuss the general structure and functions of bHLH-PAS proteins throughout the animal kingdom, including family members that do not fit neatly into the class I-class II organization. We review heterodimerization between class I and class II bHLH-PAS proteins, binding partner selectivity and functional redundancy. Finally, we discuss the evolution of bHLH-PAS proteins, and why a class I protein essential for cardiovascular development in vertebrates like chicken and fish is absent from mammals.

Keywords: aryl hydrocarbon receptor; bHLH–PAS transcription factors; hypoxia inducible factors; signalling; transcription.

Figure 1.

Structure and function of bHLH– PAS proteins.(A) bHLH–PAS transcription factors act as heterodimers, where a class I and indicated class II protein interact and bind DNA. Asterisks indicate proteins encoded by genes present in vertebrates but absent from mammals. Proteins in the indeterminate class can bind class I proteins or act independently of class I and class II proteins. (B) Cartoon structure of representative bHLH–PAS proteins indicating key functional domains: basic helix-loop-helix (bHLH), Per-Arnt-Sim motifs (PAS-A, PAS-B), transcriptional activation or repression domains (TAD, TRD), LxxLL motifs, which modulate protein–protein interactions that influence transcription.

Figure 2.. Phylogenetic tree of bHLH–PAS proteins.

Unrooted phylogenetic tree of bHLH–PAS proteins from humans and commonly studied animal models of human development. The neighbor-joining tree was built using multiple alignments of the indicated bHLH–PAS amino acid sequences. To assess the degree of confidence of the nodes, bootstrap with 1000 repetitions was performed.