title: The vitamin D receptor interacts preferentially with DRIP205-like LxxLL motifs.
abstract: The vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) through its capacity to recruit coregulatory proteins. This interaction is mediated via a coregulatory LxxLL motif. We screened a combinatorial (x)7LxxLL(x)7 phage library with purified VDR to identify peptides that displayed high affinity and selectivity for VDR. These peptides contained the consensus sequence Lx E/H x H/F P L/M/I LxxLL and exhibited significant sequence similarity to the active LxxLL box found in DRIP205. Nearly all LxxLL peptides interacted in a ligand-dependent manner directly with human VDR. However, a pattern of selectivity of the peptides for other members of the nuclear receptor family was also observed. Interestingly, the interaction between the VDR and many of the peptides was differentially sensitive to a broad assortment of VDR ligands. Finally, several of these peptides were shown to inhibit activation of a 1,25(OH)2D3-sensitive reporter gene. These studies suggest that the LxxLL motif can interact directly with the VDR and that this interaction is regulated by chemically diverse vitamin D ligands.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Zella
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Chang
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: J Wesley
authors.initials: JW
authors.lastname: Pike
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D008024:Ligands; D056913:Mediator Complex Subunit 1; D051379:Mice; D019151:Peptide Library; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014815:Vitamins / Q000494:pharmacology
chemical_list: D008024:Ligands; C538855:MED1 protein, human; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D019151:Peptide Library; D018167:Receptors, Calcitriol; D014157:Transcription Factors; D014815:Vitamins; D002117:Calcitriol