Abstract
Vitamin D Receptor (VDR) belongs to the nuclear receptor (NR) superfamily. Whereas the structure of the ligand binding domain (LBD) of VDR has been determined in great detail, the role of its amino acid residues in stabilizing the structure and ligand triggering conformational change is still under debate. There are 13 α-helices and one β-sheet in the VDR LBD and they form a three-layer sandwich structure stabilized by 10 residues. Thirty-six amino acid residues line the ligand binding pocket (LBP) and six of these residues have hydrogen-bonds linking with the ligand. In 1α,25-dihydroxyvitamin D3 signaling, H3 and H12 play an important role in the course of conformational change resulting in the provision of interfaces for dimerization, coactivator (CoA), corepressor (CoR), and hTAFII 28. In this paper we provide a detailed description of the amino acid residues stabilizing the structure and taking part in conformational change of VDR LBD according to functional domains.
Highlights
Vitamin D Receptor (VDR) belongs to the nuclear receptor (NR) superfamily and consists of 427 amino acid residues
These findings demonstrate that the Y236A mutation does not influence the ability of VDR to heterodimerize with retinoid X receptor (RXR) or to bind ligand, as alteration of this single tyrosine residue selectively impairs both 1,25(OH)2D3-dependent interaction with the activation function-2 (AF-2) CoAs steroid receptor CoA (SRC)-1, GRIP-1 and RIP-140 and the subsequent transcriptional regulatory effects of the VDR [34]
The function of VDR ligand binding domain (LBD) is related with ligand binding, nuclear localization, forming different surfaces for dimerization and interaction with CoA and CoR proteins [53]
Summary
Vitamin D Receptor (VDR) belongs to the nuclear receptor (NR) superfamily and consists of 427 amino acid residues. Like other NRs, VDR LBD includes 13 α-helical (H) structures, of which the H12 contain a short activation function-2 (AF-2) domain. It is folded into a three-layered, antiparallel α-helical sandwich that creates a ligand binding pocket (LBP). E269 does not interact directly with calcitriol and its importance is in the stabilization of the interior of the VDR structure because substituting E269 with alanine produces a significant decrease in the stability of full-length VDR LBD and the biological activity of the receptor with ligands. In hereditary vitamin D-resistant rickets (HVDRR), isoleucine is replaced by threonine at amino acid 268 (I268T) in exon 7 of the VDR gene [9,10]
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