Functionalized hormone-binding

Most of the physiologic activity of thyroid hormones is from the actions of T3. T4 can be thought of primarily as a prohormone. Eighty percent of needed T3 is derived from the conversion of T4 to T3 in peripheral tissue under the influence of tissue deiodinases. These deiodinases allow end organs to produce the amount of T3 needed to control local metabolic functions. These enzymes also catabolize T3 and T4 to biologically inactive metabolites. Thyroid hormones bind to intracellular receptors and regulate the transcription of various genes. 

The most common second messenger activated by protein/peptide hormones and catecholamines is cyclic adenosine monophosphate (cAMP). The pathway by which cAMP is formed and alters cellular function is illustrated in Figure 10.1. The process begins when the hormone binds to its receptor. These receptors are quite large and span the plasma membrane. On the cytoplasmic surface of the membrane, the receptor is associated with a G protein that serves as the transducer molecule. In other words, the G protein acts as an intermediary between the receptor and the second messengers that will alter cellular activity. These proteins are referred to as G proteins because they bind with guanosine nucleotides. In an unstimulated cell, the inactive G protein binds guanosine diphosphate (GDP). When the hormone... 

The initial step after cellular uptake of T4 is metabolic transformation to 3,5,3, -tri-iodothyronine (T3) (Fig. 52-8), which interacts with cytosolic and nuclear receptors, as well as with synaptosomal membrane binding sites of unknown function [25], Cytosolic receptors are proteins of 70 kDa that do not appear to undergo translocation to cell nuclei, nor do they appear to be nuclear proteins that have leaked out of cell nuclei during cell rupture nuclear receptors are proteins of 50 70 kDa that have both DNA-and hormone-binding domains [25,26,28],... 

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. 

The receptors for lipophilic signaling substances all belong to one protein superfamily. They are constructed in a modular fashion from domains with various lengths and functions. Starting from the N terminal, these are the regulatory domain, the DNA-binding domain, a nuclear localization sequence (see p. 228), and the hormone-binding domain (see p. 73D). 

The chaperones are used as tools in this system for regulation of activity of the steroid hormone receptors. The function of the chaperones is obviously to fix the receptor in a conformation which allows high affinity binding to the hormone and the subsequent steps of specific DNA binding and transactivation. For the steroid hormone receptors this means that they must exist in functionally different conformations. It may be a function of the chaperones to stabilize the particular conformation optimal for hormone binding. 

Why do we need vitamins Early clues came in 1935 when nicotinamide was found in NAD+ by H. von Euler and associates and in NADP+ by Warburg and Christian. Two years later, K. Lohman and P. Schuster isolated pure cocarboxylase, a dialyz-able material required for decarboxylation of pyruvate by an enzyme from yeast. It was shown to be thiamin diphosphate (Fig. 15-3). Most of the water-soluble vitamins are converted into coenzymes or are covalently bound into active sites of enzymes. Some lipid-soluble vitamins have similar functions but others, such as vitamin D and some metabolites of vitamin A, act more like hormones, binding to receptors that control gene expression or other aspects of metabolism. 

A variety of signals can be transmitted across membranes without the actual flow of a substance from one side of the membrane to the other. We saw in chapter 12 that some hormones bind to specific receptor sites on the outer surface of the plasma membrane, thereby triggering metabolic changes on the cytosolic side of the membrane. Hormonal systems that function in this way are discussed in greater detail in chapter 24. Other membrane proteins mediate specific cell-cell interactions. Sometimes these interactions merely stimulate particular types of cells to bind to one another, but often they also trigger reactions that result in proliferation or differentiation of the interacting cells. We discuss signals of this type when we consider the interaction between the B and T cells of the immune system (see Supplement 3). 

Activation of steroid hormone receptors by the hormone. In the absence of the hormone, the steroid receptors are complexed through the hormone-binding domain to another protein known as heat shock protein 90 (hsp90). Both the hormone-binding domain and the hsp90 prevent functional interaction of the receptor with DNA. Binding of the hormone frees the receptor from hsp90 and promotes dimerization of the receptor, which can then bind to the palindromic hormone response element (HRE) and activate transcription. 

All of these classes of receptors have a similar structure composed of several functional domains, including regions that bind the hormone, bind to DNA, activate transcription and allow dimerization. In the absence of hormone these receptors are usually sequestered by other proteins located either in the cytoplasm or nucleus. For example,... 

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