Faculty Collaboration Database

Quantification of the vitamin D receptor-coregulator interaction. Biochemistry 2009 Feb 24;48(7):1454-61

Date

02/03/2009

Pubmed ID

19183053

Pubmed Central ID

PMC2654718

DOI

10.1021/bi801874n

Scopus ID

2-s2.0-61749101307 (requires institutional sign-in at Scopus site)   62 Citations

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.

Author List

Teichert A, Arnold LA, Otieno S, Oda Y, Augustinaite I, Geistlinger TR, Kriwacki RW, Guy RK, Bikle DD

Author

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Base Sequence
Binding, Competitive
Biphenyl Compounds
Calcitriol
Chromatography, High Pressure Liquid
DNA Primers
Electrophoresis, Polyacrylamide Gel
Fluorescence Polarization
Ligands
Mass Spectrometry
Models, Molecular
Molecular Sequence Data
Peptide Library
Polymerase Chain Reaction
Protein Binding
Receptors, Calcitriol
Sequence Homology, Amino Acid