Thyroid hormone receptor variant alpha2. Role of the ninth heptad in dna binding, heterodimerization with retinoid X receptors, and dominant negative activity.

Thyroid hormone receptors bind DNA with highest affinity as heterodimers with retinoid X receptors, and such heterodimers generally are thought to be the biological mediators of thyroid hormone action. An alternative splice product of the thyroid hormone receptor alpha gene, thyroid hormone receptor variant alpha2, does not bind thyroid hormone and functions as a weak dominant negative inhibitor of thyroid hormone action. Thyroid hormone receptor variant alpha2 is missing one-half of the ninth heptad, a region of the bona fide receptor thought to be important for heterodimerization with retinoid X receptors. The role of the ninth heptad in heterodimerization has been evaluated further. Thyroid hormone receptor variant alpha2-retinoid X receptor heterodimers form on a subset of direct repeat response elements but not on palindromic or inverted palindromic elements. Restoration of the missing ninth heptad sequence is critical for restoring heterodimerization on the palindromic DNA, but either the ninth heptad amino acids or a stretch of alanines is equally able to restore heterodimerization on the inverted palindrome. Thus, the role of the ninth heptad in heterodimerization differs on direct repeat, palindromic, and inverted palindromic response elements, suggesting that the protein-protein interactions differ on each of these elements. The dominant negative activity of thyroid hormone receptor variant alpha2 requires DNA binding, but the relatively weak nature of the dominant negative activity is only partially explained by the weak DNA binding.