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Molecular and Cellular Biology, October 1998, p. 6001-6013, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Mechanistic Principles in NR Box-Dependent Interaction between Nuclear Hormone Receptors and the Coactivator TIF2

Jörg Leers,* Eckardt Treuter, and Jan-Åke Gustafsson

Center for Biotechnology, Department of Biosciences, Karolinska Institute, NOVUM, S-14157 Huddinge, Sweden

Received 22 December 1997/Returned for modification 17 March 1998/Accepted 6 July 1998

Nuclear hormone receptors exert transcriptional activation of target genes upon hormone induction via interactions with the basal transcription machinery. This interaction is mediated by cofactors which physically bind to receptors, thereby acting as coactivators or corepressors leading to activation or repression, respectively. Here we report the screening for and cloning of a peroxisome proliferator receptor-interacting protein, the rat homolog of TIF2. By sequence comparison with the related coactivator SRC-1, we identified three short conserved motifs (NR boxes) in both proteins which are the putative binding sites of TIF2 to nuclear hormone receptors. We demonstrate here by generation of amino acid exchanges within the NR boxes that all three boxes located in the receptor interaction domain of TIF2 are necessary and sufficient for interaction. The three boxes individually can bind to hormone receptors but display preferences in binding for certain receptors. In addition, we show that the interaction domain of TIF2 can compete with other AF-2-dependent cofactors for binding to receptors. Finally, we demonstrate cooperative binding of two TIF2 molecules to a heterodimeric nuclear receptor complex even in the presence of only one cognate ligand, indicating an allosteric effect on the heterodimeric partner upon coactivator binding.

* Corresponding author. Mailing address: Department of Biosciences, Karolinska Institute, NOVUM, S-14157 Huddinge, Sweden. Phone: 46-8-608 9147. Fax: 46-8-774 5538. E-mail: joerg.leers{at}csb.ki.se.

Molecular and Cellular Biology, October 1998, p. 6001-6013, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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