A Mechanism for Pituitary-Resistance to Thyroid Hormone (PRTH) Syndrome: a Loss in Cooperative Coactivator Contacts by Thyroid Hormone Receptor (TR)beta 2

作者：Lee Sangho; Young Briana M; Wan Wei; Chan Ivan H; Privalsky Martin L^*

来源：Molecular Endocrinology, 2011, 25(7): 1111-1125.

DOI：10.1210/me.2010-0448

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 TR beta 2 isoform is expressed in the hypothalamus and pituitary, where it plays an important role in the feedback regulation of thyroid hormone levels. TR beta 2 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 TR beta 1 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 TR beta 2 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 TR beta 2 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 TR beta 2 to a TR beta 1-like, single contact mode of coactivator binding. (Molecular Endocrinology 25: 1111-1125, 2011)

• 出版日期2011-7