Determinants for selective RAR and TR recognition of direct repeat HREs

• Published in: Genes & development Vol. 7; no. 7B; pp. 1411 - 1422
• Main Authors: PERLMANN, T, RANGARAJAN, P. N, UMESONO, K, EVANS, R. M
• Format: Journal Article
• Language: English
• Published: Cold Spring Harbor, NY Cold Spring Harbor Laboratory 01.07.1993
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Biological and medical sciences; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Cells, Cultured; DNA - metabolism; Fundamental and applied biological sciences. Psychology; Haplorhini; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Protein Binding; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Receptors, Retinoic Acid; Receptors, Thyroid Hormone - chemistry; Receptors, Thyroid Hormone - metabolism; Regulatory Sequences, Nucleic Acid; Repetitive Sequences, Nucleic Acid; Retinoid X Receptors; Transcription Factors; Transcription. Transcription factor. Splicing. Rna processing; Tretinoin - metabolism; Zinc Fingers - genetics; Human; Nuclear receptor; Transcription promoter; DNA binding protein; Molecular interaction; Retinoids; Response element; Thyroid hormone; Regulatory sequence; Transcription factor; Dimerization; Retinoic acid; Colecalciferol; Hormonal receptor
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.7.7b.1411

Recently, we have shown that receptors for vitamin D3 (VDR), thyroid hormone (TR), and retinoic acid (RAR) activate preferentially through direct repeats (DRs) spaced by 3, 4, and 5 nucleotides, respectively. In addition, the RAR can activate weakly through DRs spaced by 2 nucleotides. A common feature of RAR, TR, and VDR is their ability to heterodimerize with the retinoid X receptor (RXR) through their ligand-binding domains (LBDs) to form high-affinity DNA-binding complexes that are specific for appropriately spaced repeats. In this paper we demonstrate that selective binding of RAR-RXR and TR-RXR heterodimers to their cognate DRs is a consequence of a novel cooperative dimer interaction within the DNA-binding domains (DBDs). Accordingly, a region in the first zinc finger of the TR and RAR DBDs interacts with the second zinc finger in the RXR DBD to promote selective DNA-binding to DRs spaced by 4 and 5 nucleotides, respectively. The resulting polarity established by this interaction places RXR in the 5' position of the direct repeats. These data provide a mechanism for selective receptor recognition of a restricted set of target sequences in DR DNA and explains the structural basis for physiological specificity.