Participation of Charged Amino Acid Residues of Cytoplasmic Loops of Serpentine Type Receptors in the Process of Transmission of Hormonal Signal

Abstract

Regions of cytoplasmic loops (CL1, CL2, and CL3) and C-terminal domain (CTD) of receptors of the serpentine type, proximal to the membrane, are involved in the process of functional coupling to G-proteins. Theoretical analysis of 55 types of the G-protein-coupled receptors has shown that these regions (CL1, CL2, N- and C-terminal segments of CL3, N-terminal segment of CTD) have a significant positive charge: it amounts to 18.32 ± 0.55 in receptors of biogenic amines and muscarinic choline receptors and to 16.24 ± 0.52 in receptors of peptide and protein hormones. The value of the positive charge in the CL3 and CTD segments decreases with increase of distance from the membrane, while their charge distribution profile determines selectivity of interaction of the receptor with α-subunits of the G-proteins belonging to Gs-, Gi/0-, and Gq/11-families. Distribution of the charged amino acids in CTD of some receptors can indicate their ability to form the fourth, additional, CL due to palmitoylation of cysteine residues located in CTD. Values of predisposition to form α-helices in the CL and CTD regions of the receptors are calculated. It is shown that the predisposition to form helical structures is expressed to the greatest degree in N- and C-terminal segments of the CL3, its values felling markedly with increase of distance from the membrane. The predisposition to form the helices varies significantly both in different families of receptors (it is maximal in receptors of biogenic amines and muscarinic choline receptors) and in the receptors coupled to different families of G-proteins (it is most expressed in the receptors coupled to Gs- and Gq/11-proteins). Based on the obtained data, a probable mechanism is proposed of involvement of the cationic helices formed by the CL and CTD regions in transmission of the hormonal signal from the receptor to G-protein.