Heterodimerization preferences of thyroid hormone receptor alpha isoforms

Area of Science:

• Molecular Endocrinology
• Genetics
• Biochemistry

Background:

• Thyroid hormone receptors (TRs) are crucial nuclear receptors regulating gene expression, derived from alpha and beta genes.
• Alternative splicing of the TR alpha gene generates three isoforms: TR alpha 1, TR alpha 2, and TR alpha 3, with distinct carboxy-terminal domains.
• TR alpha 2 and TR alpha 3 possess altered dimerization domains, potentially affecting their DNA-binding and dimerization properties.

Purpose of the Study:

• To investigate the impact of altered dimerization domains in TR alpha 2 and TR alpha 3 on their DNA binding and dimerization capabilities.
• To compare the binding and heterodimerization properties of TR alpha isoforms with RXR alpha on various thyroid hormone responsive elements (TREs).

Main Methods:

• Electrophoretic mobility shift assays (EMSAs) were employed to study DNA binding and dimerization.
• Analysis focused on homodimerization, heterodimerization with RXR alpha, and binding to diverse TREs.

Main Results:

• TR alpha 1 effectively formed monomers or homodimers on specific TREs and heterodimers with RXR alpha on all tested TREs.
• TR alpha 2 and TR alpha 3 showed impaired homodimer binding but exhibited differential heterodimerization with RXR alpha on various TREs (e.g., DR4, MHC-TRE, ME, F2-TRE).
• The structural alterations in TR alpha 2 and TR alpha 3 specifically abrogated homodimer binding while modulating heterodimerization with RXR alpha.

Conclusions:

• The disrupted dimerization domains in TR alpha 2 and TR alpha 3 significantly impair their ability to form homodimers.
• Heterodimerization with RXR alpha is differentially affected by these structural changes, allowing binding to a subset of TREs.
• These findings highlight the functional consequences of alternative splicing on TR alpha isoform activity and TRE recognition.