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Volume 271, Number 45, Issue of November 8, 1996 pp. 28199-28205
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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DNA-independent and DNA-dependent Mechanisms Regulate the Differential Heterodimerization of the Isoforms of the Thyroid Hormone Receptor with Retinoid X Receptor

(Received for publication, May 8, 1996, and in revised form, July 2, 1996)

From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine, Genetics, Pharmacology, and Biochemistry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Thyroid hormone receptors (TRs) require heterodimerization with retinoid X receptor (RXR) for maximum DNA binding affinity. Interaction with RXR occurs via two dimerization interfaces, one in the DNA-binding domain and one in the C-terminal ``ninth heptad'' of the receptors. We studied the relative importance of these two dimerization domains in naturally occurring C-terminal TR variants. TR1 has a conserved ninth heptad and formed stable heterodimers with RXR in solution. TR1·RXR heterodimers bound similarly to direct repeat 4 (DR4) sites with different 5-flanking and spacer sequences. In contrast, TR2, which contains a highly divergent ninth heptad, did not interact with RXR in solution and bound as a heterodimer with RXR only to specific DR4 sequences in which the downstream half-site was the preferred octameric binding site of TR (TNAGGTCA). Although the ninth heptad of TR2 was insufficient for interaction with RXR off DNA, this region was required for DNA-dependent heterodimerization with RXR. TR3, another naturally occurring TR isoform whose ninth heptad differs from those of both TR1 and TR2, displayed intermediate behavior in heterodimerization with RXR. Thus, in the absence of a strong ninth heptad interaction an octameric downstream half-site allosterically promotes RXR heterodimerization with TR2. Differential dependence upon DNA-binding for heterodimerization with RXR may influence transcriptional regulation by TR isoforms.

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