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

Peptides in Aqueous Solutions
Regulatory Peptides as Carriers of Molecular Information

Studies on the correlation between the Amino Acid Sequence and the function of a polypeptide chain intensified in the 1990s, when a consolidated international database provided the foundation for a systematic analysis of Structure–function relationships. A Brief Overview of the Current state of the art in this field is well-warranted given the vast body of literature and the multitude of empirical approaches spanning vastly different theoretical levels.

There are two primary approaches to examining The structure of peptide chains: structural analysis and amino acid sequence analysis.

Structural analysis is a method used to investigate the overall “architecture” of polypeptide macromolecules. It allows for the identification of Structural domains within a macromolecule—discrete units of compactly folded chain regions connected by adjacent, more loose and flexible segments. Structural modules can be considered a subclass of domains. A case in point is the structure of high-mobility group Nuclear Proteins. Structural analysis has revealed such polypeptide chain folding elements as ß-barrels, transmembrane receptor loops, as well as extra- and intracellular modules.

Amino acid sequence analysis aims to rationalize the immense volume of existing data on the Introduction/19.html">Primary Structure of Polypeptides. The core method of this analysis is the identification of sequence similarities across different proteins. Comparing conserved chain regions with the Functional Characteristics of a molecule makes it possible to group numerous proteins into distinct families. For instance, G protein-coupled receptors (such as muscarinic, opioid, and adrenergic receptors) form a family sharing specific signaling and pharmacological properties.

The comparison of numerous protein structures isolated from diverse sources has revealed common features in proteins performing identical or similar Functions: their structures retain conserved Regions of the polypeptide chain. These islands of constancy amidst a sea of mutational variations are most commonly referred to as motifs, and occasionally as blocks or segments. Currently, amino acid sequence analysis is employed to classify proteins and determine their membership in specific families (Pietrokovski et al., 1996). As a rule, a macromolecular chain contains not just one, but several motifs characteristic of a particular protein family. Typically, these regions consist of 10–15 amino acid residues, though shorter ones also occur. For example, the phosphorylation center of protein kinase C has the following sequence (Bairoch et al., 1996):

Class="center">[ST]—X—[RK],

where X is any amino acid. The structural similarity of A number of proteins involved in ATP-dependent nucleic acid unwinding processes is defined by several common motifs, one of which—the so-called DEAD-box—is characteristic of most ATP-binding proteins (Pietrokovski et al., 1996):

[LІVMF](2)—D—Е—A—D—[RKEN]—X—[LIVMFYGSTN]

The statistical approach makes it possible to calculate the relative frequency of occurrence of each amino acid residue in the chain as well as the recurrence of specific amino acid combinations. Using this method, repeating regular sequences can be identified in certain proteins. For instance, in tropocollagen, every third residue is Glycine, followed by Proline or hydroxyproline. In the a-chain of fibrinogen, 31% of all Amino Acids are Serine, glycine, and proline occurring in identical repeating combinations. Regular sequences involving glycine and proline are also typical of other proteins, such as Scleroproteins, Keratins, and double-stranded Silk Fibroin. On the one hand, these sequences are optimal for forming a right-handed a-helical chain conformation and an orderly arrangement of hydrophilic and hydrophobic regions along the “faces” of this helix (see Fig. 4, Section 1.2.3). On the other hand, the predominance of glycine and proline residues in regular sequences—which are essential for peptide chain bending—facilitates the transition of macromolecules into a supercoiled conformation, in which three or seven a-helical segments twist together to form a structure resembling a three-strand or seven-strand cable (Lehninger, 1974). All these proteins perform structural (scaffolding) functions, and the regular blocks in their structure stabilize specific mechanical Properties of the macromolecule or allow for their modulation. In other words, the structure–mechanical strength relationship is quite evident for these proteins. It is therefore advisable to extend the investigation (search) for correlations between The amino acid sequence of a peptide chain and physiological functions other than mechanical ones. This objective is addressed by the statistical Analysis of the Amino acid sequences of 242 regulatory proteins belonging to the METABOLISM/31.html">Transcription factor family (Atchley et al., 2000). The study revealed that certain structural characteristics of polypeptides—the distribution of amino acid residues, their association along the chain, and the tautology of certain peptide blocks—are associated with the performance of regulatory functions, namely, the initiation of Gene transcription. This function is mediated by conserved polypeptide chain regions featuring a helix-loop-helix Morphology that specifically bind to DNA promoter sites. An information-transfer model between the two helical regions of the protein has been proposed (Atchley et al., 2000). This mechanism of peptide–DNA intermolecular interaction will be discussed in detail in Chapter 3.

Below is a comparison of the frequency characteristics and amino acid sequences of regulatory Peptides and higher-molecular-weight regulatory polypeptides (proteins).