A mechanism for pituitary-resistance to thyroid hormone (PRTH) syndrome: a loss in cooperative coactivator contacts by thyroid hormone receptor (TR)beta2.

Thyroid hormone receptors (TR) are hormone-modulated transcription factors that regulate overall metabolic rate, lipid utilization, heart rate, and development. TR are expressed as a mix of interrelated receptor isoforms. The TRβ2 isoform is expressed in the hypothalamus and pituitary, where it plays an important role in the feedback regulation of thyroid hormone levels. TRβ2 exhibits unique transcriptional properties that parallel the ability of this isoform to bind to certain coactivators cooperatively through multiple contact surfaces. The more peripherally expressed TRβ1 isoform, in contrast, appears to recruit these coactivators through a single contact mechanism. We report here that clusters of charged amino acids in the TR hormone-binding domain are required for this enhanced mode of coactivator recruitment and that mutations in these charge clusters, by disrupting TRβ2 coactivator binding, are a molecular basis for pituitary resistance to thyroid hormone, a disease characterized by inappropriate thyroid hormone feedback regulation. We propose that the charge clusters allow wild-type TRβ2 to assume a conformation compatible with its mode of multiple contact coactivator recruitment, whereas disruption of these charge clusters disrupts normal T(3) homeostasis by reducing TRβ2 to a TRβ1-like, single contact mode of coactivator binding.