Steroid hormone receptor

Steroid hormone receptors are intracellular receptors (typically cytoplasmic) that perform signal transduction for steroid hormones. Steroid hormone receptors are part of the nuclear receptor family that include a group of homologous structured receptors (type II receptors) that bind to non-steroid ligands such as thyroid hormones and vitamin A, as well as to vitamin D, and orphan receptors. All these receptors are transcription factors. Depending upon the steroid hormone that they bind, they are either located in the cytosol and move to the cell nucleus upon activation, or spend their life in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus has to do with Nuclear Localization Signals (NLS) found in a region of the receptor. In most cases this signal is covered up by heat shock proteins which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change, the heat shock proteins come off, and the receptor together the with bound hormone enter the nucleus to act upon transcription.

Types

* Type I Receptors
** Sex hormone receptors (sex hormones)
*** Androgen receptor
*** Estrogen receptor
*** Progesterone receptor
** Glucocorticoid receptor (glucocorticoids)
** Mineralocorticoid receptor (mineralocorticoids)
* Type II Receptors
** Vitamin A receptor (Vitamin A)
** Vitamin D receptor (Vitamin D)
** Retinoid receptor
** Thyroid hormone receptor
* Orphan receptors

Structure

Steroid hormone receptors share a common structure of four units that are functionally homologous, so-called "domains":

# "Variable domain": It begins at the N-terminal and is the most variable domain between the different receptors.
# "DNA binding domain": This centrally located highly conserved DNA binding domain (DBD) consists of two non-repetitive globular motifs (PDB: [http://www.rcsb.org/pdb/cgi/explore.cgi?pid=279521117229963&pdbId=1HCQ 1HCQ] ) where zinc is coordinated with four cysteine and no histidine residues. Their secondary and tertiary structure is distinct from that of classic zinc fingers. [Evans, R.M. "The steroid and thyroid hormone receptor superfamily". Science 240:889-895. 1988. PMID 3283939.] This region controls which gene will be activated. On DNA it interacts with the hormone response element (HRE).
# "Hinge region": This area controls the movement of the receptor to the nucleus.
# "Hormone binding domain": The moderately conserved ligand-binding domain (LBD) can include a nuclear localization signal, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to chaperones (namely heat shock proteins hsp90 and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformation. At the end of this domain is the C-terminal. The terminal connects the molecule to its pair in the homodimer or heterodimer. It may affect the magnitude of the response.

Only type I receptors have a heat shock protein (hsp) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II receptors have no hsp, and in contrast to the classical type I receptor are located in the cell nucleus.

There is some evidence that certain steroid hormone receptors can extend through lipid bilayer membranes at the surface of cells and might be able to interact with hormones that remain outside of cells. [Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E. "Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens." Steroids 2004;69:553-9. PMID 15288769.]

Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k and Akt kinase. [Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Ando S. "Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway." J Clin Endocrinol Metab 2004;89:1443-51. PMID 15001646.]

Functioning

Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus.

After binding to the ligand (steroid hormone), steroid receptors often form dimers. In the nucleus the complex acts as transcription factors, augmenting or suppressing transcription of particular genes by its action on DNA. As a result messenger RNA is produced that exits the nucleus and interacts with ribosomes. There, after translation of the genetic message, specific proteins are produced. These specific proteins perform a biological task.

Type II receptors are located in the nucleus. Thus their ligands pass through the cell wall and cytoplasm and enter the nucleus, where they activated the receptor without release of hsp. The activated receptor interacts with the hormone response element, and the transcription process is initiated as with type I receptors.

Action on DNA

The hormone response elements (HRE) for steroid hormone receptors are DNA sequences with the structure of a pair of palindrome or tandem sequences often separated by three nucleotides. These elements resemble each other in their length and arrangement but differ in their sequences.

A given hormone-receptor complex's ability to cause a change in the expression of the gene it regulates depends on the specific HRE sequence, the distance of HRE from the gene and the number of HRE affecting the gene. [David L. Nelson, Michael M. Cox. "Lehninger Principles of Biochemistry, Third Edition". W.H. Freeman & Company; 3rd Bk&CD edition (May 1, 2000). ISBN 1-57259-931-6]

The biological response is influenced by the amount of hormones available, the available receptor population, the dissociation rate of the hormone-receptor complex with the specific DNA site, and the replenishment of the receptor population.

See also

* Receptors
* Nuclear receptor

References

External links

* [http://www.neurosci.pharm.utoledo.edu/MBC3320/steroids.htm#receptors MBC 3320 Steroid hormones and receptors] , by Dr. William S. Messer, updated on Monday, April 3, 2000 at 6:05 p.m.
* [http://www.sbs.utexas.edu/dharma/TSM%20lectures/Steroid%20Hormone%20Receptor%20Signaling.doc Steroid Hormone Receptor Signaling] . Transcript from Ed. Ralph, A. Bradshaw and Edward A. Dennis: "Handbook of Cell Signaling". Academic press, CA, chapter 275. ISBN 0-12-124546-2. Retrieved on May 25, 2005 at 7:49 a.m. (UTC).
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