Lipophilic derivatization and its effect on the interaction of cholecystokinin (CCK) nonapeptide with phospholipids

N-terminal lipophilic derivatization of the fully active cholecystokinin analogue (Thr,Nle)-CCK-9 with the di-myristoyl-raz-thioglyceryl moiety leads to spontaneous self-aggregation of the lipopeptide into polydispersed vesicles at the liquid state. The high degree of fluidification of the vesicles favors a fast and net transfer of monomers to phospholipid bilayers even below the phase-transition temperature of the acceptor vesicles. Surprisingly, the process is accompanied by formation of peptide clusters. The peptide-rich domains exhibit a high affinity for Ca2+, a fact which may be correlated to the biological function of CCK as this hormone is known to stimulate calcium outflux from reserves in the cell membranes. Moreover, induced membrane affinity allowed to study more precisely the interaction of the CCK peptide with lipid bilayers as mimicry of cell membranes. Differently from what was observed with a similar lipogastrin derivative in which the peptide tail was found to be permanently exposed to the aqueous phase, in the case of the lipo-CCK compound insertion of its C-terminal active site into more hydrophobic compartments of the bilayer is occurring, as well as a folding into beta-type structures, thus confirming the role of cell membranes in displaying peptide hormones for specific receptor recognition.