ACYLATION OF THE ALPHA-AMINO GROUP IN NEUROPEPTIDE Y(12-36) INCREASESBINDING-AFFINITY FOR THE Y-2 RECEPTOR

Competition assays using three series of analogs of neuropeptide Y (NP Y) ( [Xaa(11)]NPY(11-36), [Xaa(12)]NPY(12-36), and [Xaa(13)]NPY(13-36) ) revealed that the binding affinity for the Y-2 receptor was consider ably lowered by truncation of residue 11. Upon acetylation or succinyl ation of the alpha-amino group, the binding affinity of [Xaa(12)]NPY(1 2-36) recovered to a level similar to that of [Xaa(13)]NPY(11-36). No significant difference was observed between the increases caused by ac etylation and those caused by succinylation, suggesting that the incre ase in binding affinity cannot be explained by the change in the net c harge at the N-terminus as a consequence of the modification. The scat tered data points on a plot of the alpha-helix content vs. IC50 of all these analogs revealed the absence of any apparent relationship, an i ndication that prior formation of the alpha-helix is not necessary for binding to the Y-2 receptor. It has been widely accepted that fewer t han 12 residues from the C-terminus are directly involved in binding o f NPY to the Y-2 receptor, while the remaining part of NPY only assist s in the adoption of a favorable conformation by the C-terminal hexape ptide for recognition by the receptor. However, the present results su ggest that the region around residue 12 does not project from the Y-2 receptor.