title: Quantification of the vitamin D receptor-coregulator interaction.
abstract: The vitamin D receptor (VDR) regulates a diverse set of genes that control processes including bone mineral homeostasis, immune function, and hair follicle cycling. Upon binding to its natural ligand, 1alpha,25(OH)(2)D(3), the VDR undergoes a conformational change that allows the release of corepressor proteins and the binding of coactivator proteins necessary for gene transcription. We report the first comprehensive evaluation of the interaction of the VDR with a library of coregulator binding motifs in the presence of two ligands, the natural ligand 1alpha,25(OH)(2)D(3) and a synthetic, nonsecosteroidal agonist LG190178. We show that the VDR has relatively high affinity for the second and third LxxLL motifs of SRC1, SRC2, and SRC3 and second LxxLL motif of DRIP205. This pattern is distinct in comparison to other nuclear receptors. The pattern of VDR-coregulator binding affinities was very similar for the two agonists investigated, suggesting that the biologic functions of LG190178 and 1alpha,25(OH)(2)D(3) are similar. Hairless binds the VDR in the presence of ligand through a LxxLL motif (Hr-1), repressing transcription in the presence and absence of ligand. The VDR binding patterns identified in this study may be used to predict functional differences among different tissues expressing different sets of coregulators, thus facilitating the goal of developing tissue- and gene-specific vitamin D response modulators.
authors.affiliation: Endocrine Unit, University of California, San Francisco, San Francisco, California 94121, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Teichert
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.forename: Steve
authors.initials: S
authors.lastname: Otieno
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oda
authors.forename: Indre
authors.initials: I
authors.lastname: Augustinaite
authors.forename: Tim R
authors.initials: TR
authors.lastname: Geistlinger
authors.forename: Richard W
authors.initials: RW
authors.lastname: Kriwacki
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D005454:Fluorescence Polarization; D008024:Ligands; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D001713:Biphenyl Compounds; D017931:DNA Primers; D008024:Ligands; D019151:Peptide Library; D018167:Receptors, Calcitriol; C526404:YR301; D002117:Calcitriol