Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Chapter V. HORMONES IN THE SYSTEM OF INTERCELLULAR INTEGRATION OF BODY FUNCTIONS

CHAPTER 23. HORMONAL REGULATION OF METABOLISM AND CELLULAR BIOLOGICAL FUNCTIONS. I. BIOCHEMICAL SYSTEMS OF INTRACELLULAR TRANSDUCTION OF HORMONAL SIGNALS

23.3. MOLECULAR AND CELLULAR MECHANISMS OF ACTION OF STEROID AND THYROID HORMONES

Hormones of the second group include Steroids (corticosteroids, Sex Hormones, vitamin D derivatives) and THYROID HORMONES.

Similar to protein-Peptide Hormones and biogenic amines (Amino Acid Derivatives), a prerequisite for the BIOLOGICAL EFFECTS OF this group of hormones is their binding to specific receptor molecules in target Tissues. The validity of the statement by Paul Ehrlich, the founder of The Theory of cellular receptors — «Corpora non agunt nisi fixata» ("Substances do not act unless bound" — Latin) — is clearly illustrated by the experimental results shown in Fig. 23.10.

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Fig. 23.10. Distribution dynamics of H³-estradiol in female rat tissues (x-axis — degree of hormone binding in tissue, cpm/g of tissue; y-axis — time after hormone administration, h): 1 — Uterus; 2 — Vagina; 3 — Liver; 4 — Blood; 5 — Muscles.

However, unlike peptide hormones and biogenic amines, the receptors for this group of hormones are localized intracellularly in the Cytosol, from which hormone-receptor complexes translocate into The Nucleus. There they interact with specific DNA sites of nuclear Chromatin, triggering the activation of genes for corresponding enzyme Proteins. While the first group of hormones activates already existing enzyme molecules, the action of steroids and thyroid hormones on target Cells stimulates The Biosynthesis of new enzyme molecules by activating the METABOLISM/31.html">Transcription of their mRNA (Fig. 23.11).

Fig. 23.11. Scheme of the Biochemical Mechanisms of action of steroid and thyroid hormones.

Accordingly, protein-peptide hormones and biogenic amines control rapid adaptation processes that require the immediate Activation of a specific biochemical pathway or physiological function (Glycogenolysis, lipolysis, Muscle contraction). In contrast, the biological action of the second group of hormones is slower (taking several hours to manifest) and is responsible for long-term adaptation processes of the body.

Structure of Steroid and Thyroid Receptors

Untransformed hormone-bound receptors are dimeric proteins with molecular weights ranging from 50 to 190 kD and sedimentation coefficients from 3.5 to 4.5 s (Table 23.2).

Table 23.2. PHYSICOCHEMICAL PROPERTIES OF cytosolic steroid Hormone Receptors (V.B. Rosen, 1984)

MOLECULAR MECHANISMS OF Action

The sequence of CELLULAR AND BIOCHEMICAL reactions through which steroid and thyroid hormones exert their biological effects is as follows:

hormone penetration into The Cell —► binding of the hormone to the cytosolic receptor —► modification (activation) of the receptor within the hormone-receptor complex —► translocation of the modified hormone-receptor complex into the nucleus —► interaction of the complex with a specific chromatin DNA site —► activation of specific genes —► mRNA transcription —► synthesis of enzyme proteins that mediate the biological effects of the hormone.

The interaction of steroid and thyroid hormone receptors with their specific ligands is determined by their molecular structure, which consists of distinct Structural and functional domains differing in Primary Structure and conformation (Fig. 23.12):

- the hormone-binding domain (consisting of 240 amino acid residues);

- the DNA-binding domain, which interacts with specific DNA sequences (consisting of 66 amino acid residues);

- the domain that binds additional transcription regulators (N-terminal domain).

Fig. 23.12. Domain Organization of protein hormone receptors: a — transcription regulator-binding domain; b — DNA-binding domain; c — hormone-binding domain.

The interaction of protein hormone receptors, which act as transcriptional activators, with DNA occurs at specific sites within the promoter regions of The Genome located upstream («to the left») of the Transcription initiation sites (approximately in the «-250 NUCLEOTIDES» region) and regulates the expression of downstream genes located «to the right» of the promoter and the +1 transcription initiation site (Fig. 23.13).

Fig. 23.13. Promoter regions interacting with steroid-receptor complexes (-250 site) and other transcription-activating proteins (stress proteins, metallothionein synthesis activators).

The ability of the hormone receptor domain to interact with specific DNA regions is determined by the Structural Features of both the receptor and the corresponding DNA sites. These receptor-responsive DNA regions exhibit a palindrome structure and consist of specific (for each receptor) nucleotide sequences of symmetric 6-base-pair repeats situated on either side of an intervening 3-nucleotide sequence (-NNN-) — the «spacer»:

The interaction of hormone-activated steroid and thyroid receptors with specific DNA regions also involves distinct Structural motifs within the receptor proteins, namely zinc fingers and globular Zn-containing domains (Fig. 23.14). These unique spatial formations are characteristic of all classes of proteins that function as transcriptional regulators (such as hormone receptors and metallothionein synthesis-activating proteins).

Fig. 23.14. Formation of zinc fingers in proteins (a) and The structure of the Zn-containing domain of the glucocorticoid receptor recognizing a specific palindromic sequence in the DNA molecule (b).

A molecular model illustrating the binding of Zn-containing domains from a dimeric glucocorticoid receptor to palindromic sites on the DNA molecule is shown in Fig. 23.15.

Fig. 23.15. Interaction of the dimeric glucocorticoid receptor protein with specific DNA sites.