The intrinsically disordered AB region: a key modulator of the molecular properties of human RXRγ

The human retinoid X receptor γ (hRXRγ) is one of three characterized RXR subtypes, transcription factors belonging to the nuclear receptor superfamily. All RXR subtypes share nearly identical structural elements, including a conserved DNA-binding domain, a D region, a ligand-binding domain, and an F region. However, each subtype possesses a unique N-terminal AB region, which modulates the transcriptional activation of target genes in a cell- and promoter-dependent manner through its ligand-independent activation function involved in protein-protein interactions. Despite the functional significance of the AB region, its structural contributions, particularly in the context of the full-length receptor, remain largely unexplored. Here, we uncover the role of the AB region of hRXRγ in modulating the molecular properties of the receptor. A comparative analysis of the full-length receptor (hRXRγ) and a deletion mutant lacking the AB region (ΔABhRXRγ) highlights the critical role of the intrinsically disordered AB region in modulating the structural and functional properties of hRXRγ, including its ability to oligomerize, its overall stability, and conformation heterogeneity. The AB region does not act as an independent unit but amalgamates with the rest of the receptor, which fine-tunes the structural variability of hRXRγ, making it responsive to environmental conditions. These findings highlight the AB region as a critical determinant of hRXRγ's structural features and, potentially, its transcriptional potential.