Premium
Conformational analysis of the Gα s protein C ‐terminal region
Author(s) -
D'ursi Anna Maria,
Albrizio Stefania,
Greco Giovanni,
Mazzeo Sonia,
Mazzoni Maria R.,
Novellino Ettore,
Rovero Paolo
Publication year - 2002
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.410
Subject(s) - heterotrimeric g protein , chemistry , peptide , stereochemistry , n terminus , c terminus , side chain , protein structure , crystallography , g protein , receptor , biophysics , peptide sequence , biochemistry , amino acid , biology , organic chemistry , gene , polymer
The C ‐terminal domain of the heterotrimeric G protein α‐subunits plays a key role in selective activation of G proteins by their cognate receptors. Several C ‐terminal fragments of Gα s (from 11 to 21 residues) were recently synthesized. The ability of these peptides to stimulate agonist binding was found to be related to their size. Gα s (380–394) is a 15‐mer peptide of intermediate length among those synthesized and tested that displays a biological activity surprisingly weak compared with that of the corresponding 21‐mer peptide, shown to be the most active. In the present investigation, Gα s (380–394) was subjected to a conformational NMR analysis in a fluorinated isotropic environment. An NMR structure, calculated on the basis of the data derived from conventional 1D and 2D homonuclear experiments, shows that the C ‐terminal residues of Gα s (380–394) are involved in a helical arrangement whose length is comparable to that of the most active 21‐mer peptide. A comparative structural refinement of the NMR structures of Gα s (380–394) and Gα s (374–394)C 379 A was performed using molecular dynamics calculations. The results give structural elements to interpret the role played by both the backbone conformation and the side chain arrangement in determining the activity of the G protein C ‐terminal fragments. The orientation of the side chains allows the peptides to assume contacts crucial for the G protein/receptor interaction. In the 15‐mer peptide the lack as well as the disorder of some N ‐terminal residues could explain the low biological activity observed. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd.