Peptide Self-Regulation of Living Systems (Facts and Hypotheses) - Shataeva L. K. 2003

Peptides in Aqueous Solutions
Tissue-Specific Regulatory Peptides
Peptides of the Immune System

The Regulation of the body's defense mechanisms is closely linked to The activity of the thymic system. Several peptide regulators responsible for T AND B lymphocyte function have been isolated from the mammalian Thymus (Hannappel et al., 1982b). Table III of the Appendix outlines the structures of the most thoroughly studied immunostimulatory Peptides. Interestingly, the Amino acid sequences of peptides with distinct specificities (thymopoietin controls the differentiation and function of T lymphocytes, whereas thymosin α₁ governs the maturation and function of B lymphocytes) share homologous KEK regions and paired glutamic acid residues (Martynov et al., 1986). Immunostimulatory activity is exhibited not only by intact molecules of thymopoietin, thymosin, and thymulin, but also by their specific fragments (Wegner et al., 1984). Thymosin β₄, which displays high activity in inhibiting macrophage migration, contains several repeating "dimeric" motifs: EK, ET, and PD. It appears that immune system peptides (ISPs), much like Neuropeptides (NPs), retain the biological activity of their fragments even after proteolytic Cleavage of the parent molecule. For instance, thymosin β₄ contains chain segments—also isolated from the thymus and designated as thymosin β₈ and thymosin β₉—that retain the activity of the full-length β₄ molecule. The homologous regions of these three peptides feature amino acid residues with charged side chains, whereas their variable segments incorporate Serine and hydrophobic amino acid residues (Hannappel et al., 1982a).

The remarkable precision with which an Amino Acid Sequence is tuned to its biological function is well illustrated by comparing the specific actions of thymopoietin and splenin with those of their synthetic analogs—the pentapeptides RKDVY and RKEVY, respectively. While thymopoietin and its pentapeptide analog selectively induce only T lymphocytes, splenin and its low-molecular-weight analog stimulate both T and B lymphocytes (Audhya et al., 1984). This functional selectivity is apparently driven by differences in the lengths of the side-chain ionic groups of aspartic and glutamic acids located adjacent to the amino group of the Lysine residue; this spatial arrangement dictates the likelihood of intramolecular salt bridge formation and accounts for the varying local dipole moments of these pentapeptides.

Table III of the Appendix omits data on The Structure of interferons—Glycoproteins with a Molecular Weight of 15–30 kDa produced by virus-infected Cells. Interferons do not prevent viral entry into the host Cell; instead, they inhibit Protein Synthesis, thereby halting viral mRNA Translation (Reem et al., 1982). HIV-associated peptides are likewise excluded from this Discussion, although some may play a regulatory role in the Immune Response during HIV infection (Gomazkov, 1995). Table III of the Appendix presents solely the STRUCTURE OF THE oligopeptide that inhibits HIV-1 proteinase and, consequently, viral Replication (Louis et al., 1998).

Another key peptide involved in defense mechanisms is ubiquitin, initially isolated from calf thymus and identified as a factor promoting the differentiation of T and B thymocytes, presumably via binding to cellular β-adrenergic receptors and subsequent adenylate cyclase activation (Goldstein et al., 1975). The amino acid sequence of ubiquitin was later elucidated (bottom row of Table III in the Appendix), revealing a region homologous to the N-terminal tetrapeptide of thymic humoral factor γ₂ (amino acid residues 50–53), as well as repeating KE and EK motifs shared with the sequences of thymosins α₁ and β₄ (Schlesinger et al., 1975). Using specific anti-ubiquitin Antibodies in radioimmunoassays, this peptide has been detected in virtually all vertebrate Tissues—most abundantly in the thymus, Brain, and Kidneys—as well as in Yeast and higher plants. The ubiquity of this peptide is matched by its remarkable polyfunctionality. One of its primary roles is to facilitate the rapid degradation of protein macromolecules. The conjugation of ubiquitin with an exogenous protein in the Cytoplasm results in peptide chain branching (bifurcation), targeting the protein for swift proteolysis by proteasomes. Consequently, cells utilize two main pathways for protein degradation: 1) ubiquitination followed by proteasomal proteolysis, and 2) lysosomal proteolysis. However, the former mechanism operates at a significantly faster rate. Notably, the cytolytic efficiency of killer T cells appears to rely heavily on ubiquitin activity (Wilkinson, Audhya, 1981).

The ability of ubiquitin to attach to the ε-amino groups of polypeptide lysine residues underpins its regulatory properties, which are manifested not only in the cytoplasm but also at The Cell membrane (De Bold et al., 1981). It was later demonstrated that ubiquitin also performs specific Functions within Chromatin, participating in The regulation of METABOLISM/36.html">DNA replication and Transcription inside the Cell Nucleus. Furthermore, the degradation of cyclins—the regulatory Proteins governing the Cell Division cycle—is likewise mediated through ubiquitination.