5.2 HNF4α2 (P1a-α2) protein partners
Some studies have shown interactions between the P1a-α2 AF-1 domain and proteins involved in regulating transcription, including TBP, TFIIB, TAFII3, TAFII31, TAFII80, TFIIH-p62, CBP, transcriptional adaptor 2 (ADA2) and positive cofactor 4 (PC4) (Figure 2). These interactions are mediated by hydrophobic and aromatic residues localized between amino acids 1-12 (Tyr6) and 13-24 (Tyr14, Lys10, Lys17, and Phe19) of the P1a-α2 AF-1 domain [52]. Although these interactions could occur with other HNF4α isoforms that contain the AF-1 domain, it is unclear whether there are structural differences in other isoforms that could influence these interactions. For example, it was observed that P1a-α2 AF-1 interaction with the C/H1 domain of CBP generates significantly higher increase in transcriptional activity when compared to the P1a-α1 isoform, due to a greater affinity of P1a-α2 for CBP [63]. This affinity could be related to the insertion of 10 amino acids in the F domain of P1a-α2 (Figure 1B), which would generate a conformational change in the protein to prevent the blockade this domain typically exerts for the interaction with coactivators. Similar observations were made for the interaction between P1a-α2 and NCOA2, for which transcriptional activation was reported to be seven times stronger for P1a-α2 compared to P1a-α1 [26]. It was also suggested that P1a-α2 interacts with activator protein 1 (AP-1), with the biological consequence of reducing the growth of intestinal tumor cells [50]. Although ChIP-seq analyses suggested an interaction between these two proteins, a direct physical interaction was not confirmed in this context. Other studies have proposed the formation of a direct interacting protein complex between peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and P1a-α2, this interaction impacting gluconeogenesis and glucose homeostasis in the liver [64].