Protein Phosphatases 1 and 2A Regulate the Transcriptional and DNA Binding Activities of Retinoic Acid Receptors

Abstract Retinoic acid receptors (RARs) as a functional heterodimer with retinoid X receptors (RXRs), bind a diverse series of RA-response elements (RAREs) in regulated genes. Among them, the non-canonical DR0 elements are bound by RXR–RAR with comparable affinities to DR5 elements but DR0 elements do not act transcriptionally as independent RAREs. In this work, we present structural insights for the recognition of DR5 and DR0 elements by RXR–RAR heterodimer using x-ray crystallography, small angle x-ray scattering, and hydrogen/deuterium exchange coupled to mass spectrometry. We solved the crystal structures of RXR–RAR DNA-binding domain in complex with the Rarb2 DR5 and RXR–RXR DNA-binding domain in complex with Hoxb13 DR0. While cooperative binding was observed on DR5, the two molecules bound non-cooperatively on DR0 on opposite sides of the DNA. In addition, our data unveil the structural organization and dynamics of the multi-domain RXR–RAR DNA complexes providing evidence for DNA-dependent allosteric communication between domains. Differential binding modes between DR0 and DR5 were observed leading to differences in conformation and structural dynamics of the multi-domain RXR–RAR DNA complexes. These results reveal that the topological organization of the RAR binding element confer regulatory information by modulating the overall topology and structural dynamics of the RXR–RAR heterodimers.

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Effect of 1,10-phenanthroline on DNA binding of 1,25-dihydroxyvitamin D receptors and characterization and regulation of retinoic acid receptors in rat osteosarcoma cells

10.31274/rtd-180813-12141 ◽

1991 ◽

Author(s):

Kevin Brady Atkins

Keyword(s):

Retinoic Acid ◽

Dna Binding ◽

Retinoic Acid Receptors ◽

Osteosarcoma Cells ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

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Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors.

Molecular and Cellular Biology ◽

10.1128/mcb.12.9.4153 ◽

1992 ◽

Vol 12 (9) ◽

pp. 4153-4163 ◽

Cited By ~ 229

Author(s):

A J Cooney ◽

S Y Tsai ◽

B W O'Malley ◽

M J Tsai

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Retinoic Acid ◽

Thyroid Hormone ◽

Dna Binding ◽

Vitamin D3 ◽

Retinoic Acid Receptors ◽

Response Elements ◽

Upstream Promoter ◽

Chicken Ovalbumin

Alignment of natural chicken ovalbumin upstream promoter transcription factor (COUP-TF) response elements shows that, in addition to the predominant direct repeat of the GGTCA motif with a 2-bp spacing, there are other functional COUP elements with variations in the GGTCA orientation and spacing. We systematically analyzed the binding of in vitro-synthesized COUP-TFs and showed that COUP-TF is capable of binding to oligonucleotides containing both direct repeats and palindromes and with different spacings of the GGTCA repeats. Subsequently, we analyzed four possible mechanisms proposed to explain how COUP-TF could bind to these spatial variations of the GGTCA repeat. We demonstrated that the functional DNA-binding form of COUP-TF is a dimer which requires two GGTCA half-sites to bind DNA. We demonstrated that the COUP-TF dimer undergoes a remarkable structural adaptation to accommodate binding to these spatial variants of the GGTCA repeats. A functional consequence of the promiscuous DNA binding of COUP-TF is its ability to down-regulate hormonal induction of target gene expression by other members of the steroid-thyroid hormone receptor superfamily such as the vitamin D3, thyroid hormone, and retinoic acid receptors. Our data indicate that COUP-TF may have an important role in hormonal regulation of gene expression by these receptors.

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Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors

Molecular and Cellular Biology ◽

10.1128/mcb.12.9.4153-4163.1992 ◽

1992 ◽

Vol 12 (9) ◽

pp. 4153-4163

Author(s):

A J Cooney ◽

S Y Tsai ◽

B W O'Malley ◽

M J Tsai

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Retinoic Acid ◽

Thyroid Hormone ◽

Dna Binding ◽

Vitamin D3 ◽

Retinoic Acid Receptors ◽

Response Elements ◽

Upstream Promoter ◽

Chicken Ovalbumin

Alignment of natural chicken ovalbumin upstream promoter transcription factor (COUP-TF) response elements shows that, in addition to the predominant direct repeat of the GGTCA motif with a 2-bp spacing, there are other functional COUP elements with variations in the GGTCA orientation and spacing. We systematically analyzed the binding of in vitro-synthesized COUP-TFs and showed that COUP-TF is capable of binding to oligonucleotides containing both direct repeats and palindromes and with different spacings of the GGTCA repeats. Subsequently, we analyzed four possible mechanisms proposed to explain how COUP-TF could bind to these spatial variations of the GGTCA repeat. We demonstrated that the functional DNA-binding form of COUP-TF is a dimer which requires two GGTCA half-sites to bind DNA. We demonstrated that the COUP-TF dimer undergoes a remarkable structural adaptation to accommodate binding to these spatial variants of the GGTCA repeats. A functional consequence of the promiscuous DNA binding of COUP-TF is its ability to down-regulate hormonal induction of target gene expression by other members of the steroid-thyroid hormone receptor superfamily such as the vitamin D3, thyroid hormone, and retinoic acid receptors. Our data indicate that COUP-TF may have an important role in hormonal regulation of gene expression by these receptors.

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