receptors. Within the target organs in which the steroids bind, the steroid molecules
exert their influence directly on protein synthesis, at the level of transcription of the
genetic message. Steroid hormones work primarily by regulating tissue-specific gene
expression; the hormones enter the nucleus of a cell, bind to target genes in the DNA
of that cell, and subsequently influence protein synthesis. Although steroids may also
affect other cellular processes by influencing various enzyme systems through cAMP-
dependent protein kinases, their effects on protein synthesis are of primary importance.
While the macromolecules and target tissues involved show extreme specificity
for the appropriate steroid hormones and their congeners, the general scheme of the
steroid–receptor mechanism is remarkably uniform. We can therefore deal with this
receptor model in a general way, mentioning specific details as appropriate in the sub-
sections of this chapter.
The general steroid–receptor hypothesis is based mainly on estrogen and proges-
terone receptors. The currently accepted mechanism is unique and consists of several
steps at different subcellular structures:
- Cytoplasmic receptor activation
- Translocation of the hormone–receptor complex to the nucleus
- Binding of the complex to DNA acceptor sites
- Activation of transcription and influencing protein synthesis
The steroid hormones are transported to their target cells via the bloodstream in a
protein-bound form, but diffuse into the cell as free steroids. At this point, they encounter
a cytoplasmic steroid receptor protein. The complement DNAs (cDNAs) of all the
major steroid receptors have been cloned, providing the complete amino acid sequence
of each. These receptors are large proteins; the estrogen receptor, for example, has a
molecular weight of approximately 75,000. The general model of the steroid receptor
protein consists of several functional domains. The “E” domain (ligand binding region)
is composed of the C-terminal 250 amino acids; this section has the steroid binding site
and additional sites for binding to chaperone proteins (discussed in the next paragraph).
The “D” domain (hinge region), located adjacent to the E domain, is involved with the
translocation of the steroid–receptor complex into the nucleus of the target cell. Next,
the “C” domain (DNA binding region) is made up of 70 amino acids clumped into two
finger-shaped regions, each coordinated with a Zn ion; these so-called zinc fingers are
crucial to the process whereby the steroid recognizes and binds to the DNA once the
nucleus has been penetrated. Finally, at the N-terminal of the steroid receptor protein is
the “A/B” domain (DNA modulator region), which enables the steroid–receptor com-
plex that has bound to the DNA to activate genes and initiate transcription.
Upon entering the cell, the steroid molecule initially binds to the steroid receptor
protein (E domain) to form the steroid-hormone–receptor complex. This complex con-
comitantly binds to an additional eight or more other peptides (also via the E domain);
these peptides are termed chaperone peptidesand consist of macromolecules such as
heat shock proteins(e.g., hsp70, hsp90). The chaperone peptides help to twist and turn
the steroid receptor protein into an improved three-dimensional shape for final and
optimal binding of the steroid molecule. Following binding of the chaperone peptides,
the steroid-hormone–receptor complex becomes a “mature steroid-hormone–receptor
HORMONES AND THEIR RECEPTORS 313