CASE FILES: BIOCHEMISTRY
acid. Members of this receptor superfamily contain a DNA-binding domain
responsible for binding to hormone response elements contained within the
promoters of target genes. In addition, members of this superfamily contain
a region responsible for specific binding to the hormone or biologically active
agent. DNA-binding specificity is mediated by receptor sequence motifs
owing to their chelation of one zinc ion per loop, or
In the case of thyroid hormone, receptors bind thyroid response elements
(TREs). Thyroid-hormone receptors can bind TREs as monomers, as homod-
imers, or as heterodimers with the retinoid X receptor, another member of this
superfamily. The latter exhibits the highest DNA-binding affinity and is the
major functional form of the receptor.
In essence, these receptors serve as hormone-activated transcription
factors that directly regulate transcription of messenger ribonucleic acid
(mRNA) from target genes. In contrast to other members of this superfamily,
thyroid hormone receptors bind their sites on the promoter regions of DNA in
the absence of bound hormone, usually resulting in transcriptional repression.
Binding of thyroid hormone triggers a conformational change in the
receptor, converting it to a transcriptional activator. In this state, it is com-
petent to bind a group of coactivator proteins including histone transacetylase,
an activity that serves to create a more open configuration on adjacent chro-
matin. Mammalian thyroid receptors are encoded by two different genes, each
of which can be alternatively spliced, yielding four different receptor isoforms.
These isoforms differ in their functional characteristics as well as their tissue-
specific and developmental stage-dependent expression, underscoring the
complexity of the multiple physiologic effects of thyroid hormones.
C O M P R E H E N SIO N Q U E ST IO N S
[45.1] A 25-year old female sought treatment for her constant fatigue,
lethargy, and depression. She was small in stature and had previously
been diagnosed with attention-deficit disorder. On physical examina-
tion she was found to have an enlarged thyroid gland (goiter). Blood
tests revealed elevated levels of T3, T4, and TSH, yet she did not exhibit
typical symptoms of hyperthyroidism. Which one of the following pos-
sibilities offers the most likely explanation of her symptoms?
A. Thyroid hormone overproduction because of a thyroid gland tumor
B. Hypersecretion of TSH because of a pituitary tumor
C. Genetic alteration in the thyroid receptor reducing its ability to
bind thyroid hormone
D. Mutation in the TSH receptor in the thyroid gland reducing its ability
to bind TSH
E. Iodide deficiency in the diet