Signal Protein-Derived Peptides as Functional Probes and Regulators of Intracellular Signaling

The functionally important regions of signal proteins participating in their specific interaction and responsible for transduction of hormonal signal into cell are rather short in length, having, as a rule, 8 to 20 amino acid residues. Synthetic peptides corresponding to these regions are able to mimic the activated form of full-size signal protein and to trigger signaling cascades in the absence of hormonal stimulus. They modulate protein-protein interaction and influence the activity of signal proteins followed by changes in their regulatory and catalytic sites. The present review is devoted to the achievements and perspectives of the study of signal protein-derived peptides and to their application as selective and effective regulators of hormonal signaling systems in vitro and in vivo. Attention is focused on the structure, biological activity, and molecular mechanisms of action of peptides, derivatives of the receptors, G protein α subunits, and the enzymes generating second messengers. 1. Introduction The transduction of signals generated by hormones and hormone-like substances of different nature to intracellular effector proteins controlling the fundamental cellular processes requires coordinated activity of many signal proteins, components of a wide spectrum of G protein-coupled and G protein-independent signaling systems, and has several steps in common. The first step is the recognition and specific binding of ligands with extracellular domains of sensors represented by some families of transmembrane proteins, such as the G protein-coupled receptors (GPCRs) seven times penetrating the plasma membrane, the tyrosine kinase receptors having a single transmembrane region (TM) and intracellular domain possessing the intrinsic tyrosine kinase activity, the natriuretic peptide receptors including the membrane-bound guanylyl cyclases, and natriuretic peptide clearance receptor (NPR-C) lacking cyclase activity. The ligand binding is responsible for alteration of conformation of the extracellular regions of receptor and, in the case of GPCRs, for changes of the three-dimensional structure of receptor transmembrane channel (TMC) participating in formation of the ligand-binding site, which starts to transfer the external signal across the plasma membrane and triggers intracellular signaling cascade [1–3]. In the case of G protein-coupled signaling systems the second step of signal transduction is the interaction of intracellular regions of ligand-activated receptor with α subunit and/or βγ dimer of heterotrimeric G protein in inactive, GDP-bound, state,