Steroid hormones, binding

Several criteria determine whether a steroid-hormone-binding site is a putative receptor. First, the steroid-hormone-binding site must be present in hormone-responsive tissues or brain regions, and absent from nonresponsive ones. Second, it should bind steroids that are either active agonists or effective antagonists of the hormone effect, and should not bind steroids that are inactive in either sense. 

An account of the principles which help to understand how hormones achieve their roles in the body is given in Chapter 12. The understanding is based on separation of the effects of hormones into three components the action, the effects (biochemical and physiological) and the function. A steroid hormone binds to a cytosolic intracellular receptor, which then moves into the nucleus where it binds to DNA at a specific site (the steroid response element) and activates genes which result in the formation of proteins that elicit biochemical and physiological effects. This is discussed for cortisol in Chapter 12 and aldosterone in Chapter 22. Much of the interest in the reproductive steroid hormones is in the physiological effects and how these account for their functions. 

Steroid Hormones. Generally, steroid hormones arc mctaholically short-lived steroids produced in small amounts by various endocrine glands. They serve as chemical messengers that regulate a variety of physiological and metabolic activities in vertehrates. Steroid hormones bind to soluble, intracellular receptor molecules. In the nucleus of... 

FIGURE 28-2 Primary cellular locations of hormone receptors. Peptide hormones tend to bind to surface membrane receptors (site 0 steroid hormones bind to cytosolic receptors [site 10 and thyroid hormones bind to receptors in the cell nucleus [site III). 

Figure 17.4 Intracellular steroid receptor activation by hormone ligands, (a) Steroid hormones diffuse across the cell membrane into the cell. (b) Steroid hormone receptors in the basal state bound to accessory proteins, (c) Steroid hormones bind to receptors and accessory proteins are dissociated from the receptors. (d) Hormone receptor complexes dimerize. (e) Dimer complexes enter the nucleus and initiate transcription of responsive genes.

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

Fig. 1. Domain model of the receptor. The DNA binding domain is in the centre and the steroid hormone binding domain (S) is to the right. The domains are not drawn to proportion. The arrows point at hinge regions between the domains which are easily cleaved by proteases like chymotrypsin ( ) or trypsin (o).

Correct answer = E. All steroid hormones bind to receptors in the nucleus or the cytosol. 

Calcitriol acts like a steroid hormone, binding to, and activating, nuclear receptors that modulate gene expression. More than 50 genes are known to be regulated by calcitriol (see Table 3.3), but vitamin D response elements have only been identified in a relatively small number, including calcidiol 1-hydroxylase and 24-hydroxylase calbindin, a calcium binding protein in the... 

Steroid hormones bind to and activate receptor molecules that serve as transcription factors to regulate gene expression (Section 31.3.1). These small, relatively similar molecules are able to have greatly differing effects because the slight structural differences among them allow interactions with specific receptor molecules. 

Cadmium is a divalent metal ion. It is a toxic metal ion that can induce damage to the reproductive system. In general, cadmium can bind to sites of proteins that are normally used to bind zinc, (t is possible that the cadmium-induced damage to the reproductive system results from the binding to the zinc fingers of the steroid hormone-binding proteins. 

Steroid hormone binding proteins, 393 Steroid hormones, 807 synthesis, 747 r.tnc fingers and, 805 Sterol response elemenl, 367-368 Sterol response element binding protein (SREBF), 367-368 Stctichiometry, 275 Stomach... 

Liquid-liquid partition chromatography techniques based on aqueous-aqueous systems have successfully been employed in the fractionation of crude human serum, purification of steroid hormone-binding proteins from human serum, isolation of basic proteins from crude bacterial extracts, purification of immunoglobulins and monoclonal antibodies, DNA fractionations by size, topology and base sequence, as well as the isolation of soluble and ribosomal RNAs in preparative amounts from bulky mixtures [10]. Highspeed CCC using PEG-dextran system has also been employed in the separation of proteins [6]. 

C. Steroid hormones bind to receptors that subsequently bind to DNA, as do 1,25-DHC, thyroid hormone, and retinoic acid (from vitamin A). 

Hormone transport. Steroid hormones bind to carrier proteins and are transported in the blood stream to their required sites. At these sites, the hormones transfer to storage sites while they await release for use. When these carrier proteins are interfered with, the hormones are not delivered to the required sites. 

Steroid hormones perform many functions in cells, one of which is to activate gene expression by binding to steroid receptors, proteins in the cytoplasm that, when activated, act as factors that initiate transcription. All steroid hormones are derived from cholesterol and, as a result, have similar chemical structures. Steroid hormones differ one from another primarily in hydrox-ylation of particular carbon atoms and by aromatiza-tion of the steroid A ring of the molecule. Once a steroid hormone binds to a steroid receptor protein, the complex undergoes a series of structural changes that result in the complex binding to DNA at a particular sequence called a steroid response element (SRE)... 

Only 2% of total plasma testosterone is present in the physiologically active unbound state. The remaining testosterone is reversibly bound to a steroid hormone-binding globulin. The unbound testosterone or androgen precursors penetrate the prostatic cell by passive diffusion and are converted to DHT by 5-o -reductase. DHT subsequently binds with a specific cytoplasmic receptor. This DHT-receptor complex is then transported to the nucleus of the cell, where transcription and ultimately translation of stored genetic material occur. 

Simmer, R. C. M., Means, A. R., and Clark, J. H., Estrogen modulation of nuclear-associated steroid hormone binding, Endocrinology, 115, 1197, 1984. 

Steroid hormones are often present in cells in low concentrations. This makes them difficult to isolate and identify. It is sometimes easier to isolate the proteins to which they bind by using affinity chromatography. (Refer to Biochemical Methods 5.1.) Explain how you would use this technique to isolate a protein suspected of steroid hormone binding. 

The Gla-containing proteins of the blood coagulation system are all modular with the Gla-domain N terminal. Factors VII, IX, and X and protein C form a group with the same domain structure. The Gla domain is followed by two EGF-like domains, of which the first one also binds calcium (see Section IV.C), and a serine protease domain, also with a calcium-binding site (see Section IV.D). Prothrombin and protein S have somewhat different domain structures (145, 146). In prothrombin the Gla domain is followed by a hexapeptide with a disulfide loop, two kringle domains, and the C-terminal serine protease domain. In protein S the Gla domain is followed by the thrombin-sensitive loop, four EGF-like domains, and the C-terminal domain that is homologous to plasma steroid hormone-binding proteins. 

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