Lipid-soluble hormones, such as steroid hormones (estrogen and cortisol) or thyroid hormones, can easily diffuse across the cell membrane. Their actions begin deep inside the cell, where they interact with specialized proteins called nuclear receptors. These receptors are ligand-activated transcription factors that directly control gene expression. This unique signaling mechanism allows the hormone to bypass traditional cell surface receptors and directly influence the cell’s genetic machinery.
Why the Binding Location Varies
The initial location where a hormone meets its nuclear receptor is not uniform across all hormone types. The variation in binding location stems from the existence of two main classes of nuclear receptors, known as Type I and Type II. These two groups differ fundamentally in their default positioning within the cell before the hormone arrives. Type I receptors are typically found inactive in the cytoplasm, held in a dormant state by chaperone proteins. In contrast, Type II receptors are constitutively bound to the cell’s DNA within the nucleus.
The Cytoplasmic Process: Type I Receptors
The mechanism for Type I receptors, which includes those for glucocorticoids, androgens, and estrogens, begins in the cytoplasm of the target cell. In their inactive state, these receptors are associated with stabilizing proteins, most notably Heat Shock Proteins (HSPs) like HSP90, which maintain the receptor in a conformation ready for hormone recognition. The hormone diffuses into the cell and first binds to its cognate receptor while it is still tethered to the HSP complex. This binding event causes a conformational change, leading to the dissociation and release of the chaperone proteins.
The newly activated receptor then undergoes dimerization, pairing up with another identical receptor molecule to form a homodimer. This complex exposes a specific sequence that directs its movement into the cell nucleus, a process known as translocation. Once inside the nucleus, the homodimer seeks out specific DNA sequences known as Hormone Response Elements (HREs). Binding to the HREs allows the activated hormone-receptor complex to recruit coactivator proteins, initiating the transcription of the target gene.
The Nuclear Process: Type II Receptors
Type II receptors, which mediate the effects of thyroid hormone and retinoic acid, follow a fundamentally different path, with the hormone binding occurring directly inside the nucleus. These receptors are already situated on the DNA of the target genes, even in the absence of their hormone ligand. In their unliganded state, Type II receptors typically form a heterodimer with the Retinoid X Receptor (RXR). This receptor-DNA complex, in its inactive form, is bound to corepressor proteins that actively suppress gene transcription.
The lipid-soluble hormone must first diffuse through the cytoplasm and the nuclear membrane to reach the receptor complex in the nucleus. Hormone binding to the receptor triggers a structural change. This conformational shift causes the corepressor proteins to detach from the receptor complex. Their departure is immediately followed by the recruitment of coactivator proteins, which modify the surrounding chromatin structure. The exchange of corepressors for coactivators switches the receptor complex from a transcriptional repressor to an activator, initiating the transcription of the target genes.