The role of the T-box for the function of the vitamin D receptor on different types of response elements

The nuclear hormone 1 alpha,25-dihydroxyvitamin D-3 (VD) mainly functions t hrough a heterodimer formed between the VD receptor (VDR) and the retinoid X receptor (RXR). This transcription factor complex specifically recognizes DNA sequences, referred to as VD response elements (VDREs), that are forme d by two hexameric core binding motifs arranged either as direct repeats sp aced by 3 nt (DR3) or inverted palindromes with nine intervening nucleotide s (IP9). Gel shift clipping assays provided the first evidence that VDR-RXR heterodimers form different conformations on these two types of VDREs. Sin ce the T-box within the C-terminal extension of the receptor DNA binding do main (DBD) was previously shown to form a dimerization interface with the p artner receptor DBD when bound to DR-type response elements, all six amino acid residues of the VDR T-box were investigated for their role in VDR-RXR heterodimer complex formation on DR3- and IP9-type VDREs, interestingly, th e residue Phe93 (F93) was found to be critical on both types of VDREs, wher eas the role of the residue Ile94 (I94) was found to depend on ionic streng th of the binding reaction and the nature of the VDRE. However, under physi ological conditions I94 was also shown to be critical on both VDRE types. T he monitored differences between the two VDR-containing protein-DNA complex es helps in an understanding of the differential action of the nuclear horm one VD and its therapeutically important analogues.