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Truncated variants of thyroid hormone receptor beta display disease-inflicting malfunctioning at cellular level.
Rehman, Ghausiya; Kashyap, Jyoti; Srivastav, Amit Kumar; Rizvi, Sheeba; Kumar, Umesh; Tyagi, Rakesh K.
Afiliação
  • Rehman G; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
  • Kashyap J; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
  • Srivastav AK; School of Nano Sciences, Central University of Gujarat, Gandhinagar, Gujarat, 382030, India.
  • Rizvi S; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India.
  • Kumar U; School of Nano Sciences, Central University of Gujarat, Gandhinagar, Gujarat, 382030, India; Nutrition Biology Department, School of Interdisciplinary and Applied Sciences, Central University of Haryana, Mahendergarh, Haryana, 123031, India.
  • Tyagi RK; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, 110067, India. Electronic address: rktyagi@yahoo.com.
Exp Cell Res ; 437(2): 114017, 2024 Apr 15.
Article em En | MEDLINE | ID: mdl-38555013
ABSTRACT
Thyroid hormone receptor ß (THRß) is a member of the nuclear receptor superfamily of ligand-modulated transcription factors. Upon ligand binding, THRß sequentially recruits the components of transcriptional machinery to modulate target gene expression. In addition to regulating diverse physiological processes, THRß plays a crucial role in hypothalamus-pituitary-thyroid axis feedback regulation. Anomalies in THRß gene/protein structure are associated with onset of diverse disease states. In this study, we investigated disease-inflicting truncated variants of THRß using in-silico analysis and cell-based assays. We examined the THRß truncated variants on multiple test parameters, including subcellular localization, ligand-receptor interactions, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions. Moreover, molecular dynamic simulation approaches predicted that shortened THRß-LBD due to point mutations contributes proportionally to the loss of structural integrity and receptor stability. Deviant subcellular localization and compromised transcriptional function were apparent with these truncated variants. Present study shows that 'mitotic bookmarking' property of some THRß variants is also affected. The study highlights that structural and conformational attributes of THRß are necessary for normal receptor functioning, and any deviations may contribute to the underlying cause of the inflicted diseases. We anticipate that insights derived herein may contribute to improved mechanistic understanding to assess disease predisposition.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Receptores beta dos Hormônios Tireóideos Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fatores de Transcrição / Receptores beta dos Hormônios Tireóideos Idioma: En Ano de publicação: 2024 Tipo de documento: Article