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Mapping the Domains of the Interaction of the Vitamin D Receptor and Steroid Receptor Coactivator-1

Departments of Medicine and Pediatrics Medical University of South Carolina Department of Veterans Affairs Medical Center Charleston, South Carolina 29401-5799

The vitamin D receptor (VDR) binds to the vitamin D response element (VDRE) and mediates the effects of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃], on gene expression. The VDR binds to the VDRE as a heterodimeric complex with retinoid X receptor. In the present study, we have used a yeast two-hybrid system to clone complementary DNA that codes for VDR-interacting protein(s). We found that the human steroid receptor coactivator-1 (SRC-1) interacts with the VDR in a ligand-dependent manner, as demonstrated by ß-galactosidase production. The interaction of the VDR and the SRC-1 takes place at physiological concentrations of 1,25(OH)₂D₃. A 48.2-fold stimulation of ß-galactosidase activity was observed in the presence of 10^-10 M 1,25-(OH)₂D₃. In addition, a direct interaction between the ligand-activated glutathione-S-transferase-VDR and ³⁵S-labeled SRC-1 was observed in vitro. Deletion-mutation analysis of the VDR established that the ligand-dependent activation domain (AF-2) of the VDR is required for the interaction with SRC-1. One deletion mutant, pGVDR-(1–418), bound the ligand but failed to interact with the SRC-1, whereas another deletion mutant, pGVDR-(1–423), bound the ligand and interacted with the SRC-1. We demonstrated that all the deletion mutants were expressed as analyzed by a Gal⁴ DNA-binding domain antibody. Deletion mutation analysis of the SRC-1 demonstrated that 27 amino acids (DPCNTNPTPMTKATPEEIKLEAQS-QFT) of the SRC-1 are essential for interaction with the AF-2 motif of the VDR.

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