Structural organization of binding determinants in the molecule of insulin-like growth factor-I (IGF-I)

Insulin-like growth factor I (IGF-I) is a peptide related to insulin and IGF-II. These three related peptides produce similar biological effects, but each of them has its irreplaceable physiological significance in the organism. Multisided functional role of IGF-I in the organism is due to its unique binding properties. Specifically, but with different degree of affinity, it is able to interact with three receptors (IGF-I-receptor, insulin receptor, and IGF-II-receptor) and six binding proteins (IGFBP 1–6). To interact with each of the above objects, the IGF-I molecule contains individual structural determinants—binding domains (BD) providing strict specificity of interaction with them. Responsible for the IGF-I biological effects and binding with IGF-I-receptor is α-domain, for binding with insulin receptor—β-, EGF-II—γ-, while with all BP—δ-BD, respectively. Results of experimental study of binding domains not always can be estimated unanimously. The proposed by the author system of criteria for evaluation of changes in affinity of the IGF-I analogies allows unraveling the structural organization of each of the domains and tracing dependence on it of the peptide affinity to the particular object. This work considers composition, organization, and principle of formation of affinity of three binding IGF-I domains (α-, γ-, and δ-BD). The α-domain includes three tyrosines from three different molecule sites (B-24, C-31, and A-60) disposed spatially in the direct vicinity on its one surface. The β-domain also is considered as the domain participating in the high-affinity interaction; by composition and location in molecule it principally differs from α-BD, with the structural organization that so far has not been deciphered. Analyzed in detail is the key significance of the N-terminal site of the B-chain—the linear site of the domain—for binding of IGF-I with BP, functional heterogeneity of its constituent residues, and the characteristic principle of formation of affinity to BP. Analysis indicates a probability of the second δ-BD, quite possibly not the only one, and a high sensitivity of the domain to configuration of the IGH-I molecule surface. Structural organization and peculiarities of formation of affinity in the γ-domain are studied the best in three related peptides; it consists of two linearly exposed sites of A-chain. Composition of the site S-1 A (Phen8, Arg9, Ser10) provides a possibility of binding the ligand with IGF-I-receptor, while the level of affinity to it depends on the composition of S-2. The S-2 A composition (Arg14, Arg15) determines the low affinity of IGF-I to the IGF-II-receptor. The clear functioning of IGF-I and elimination of mixture of functions at the level of the binding activity depend on the spatial autonomy of BD of different nature, difference in structural organization of each of the domains, and a peculiarity of principles of formation of affinity in each case. The spatial coordination of several BD sites is the condition for transmission of the “structural signal“ by regulatory peptide. The performed analysis provides the direct notion of dependence of the binding ability of the IGF-I molecule that has BD of different nature on their structural peculiarities and allows using the revealed regularities at searching for BD in the newly discovered insulinlike peptides.