A mechanism for pituitary-resistance to thyroid hormone (PRTH) syndrome: a loss in cooperative coactivator contacts by thyroid hormone receptor (TR)beta2.
Mol Endocrinol
; 25(7): 1111-25, 2011 Jul.
Article
en En
| MEDLINE
| ID: mdl-21622532
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 TRß2 isoform is expressed in the hypothalamus and pituitary, where it plays an important role in the feedback regulation of thyroid hormone levels. TRß2 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 TRß1 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 TRß2 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 TRß2 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 TRß2 to a TRß1-like, single contact mode of coactivator binding.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Síndrome de Resistencia a Hormonas Tiroideas
/
Receptores beta de Hormona Tiroidea
/
Coactivador 1 de Receptor Nuclear
Límite:
Humans
Idioma:
En
Revista:
Mol Endocrinol
Asunto de la revista:
BIOLOGIA MOLECULAR
/
ENDOCRINOLOGIA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos