Strongly Altered Receptor Binding Properties in PP and NPY Chimeras Are Accompanied by Changes in Structure and Membrane Binding

Neuropeptide Y (NPY) and the pancreatic polypeptide (PP) are members of the neuropeptide Y family of hormones. They bind to the Y receptors with very different affinities:  Whereas PP is highly selective for the Y4 receptor, NPY displays highest affinites for Y1, Y2, and Y5 receptor subtypes. Introducing the NPY segment 19−23 into PP leads to an increase in affinity at the Y1 and Y2 receptor subtypes whereas the exchange of this segment from PP into NPY leads to a large decrease in affinity at all receptor subtypes. PP displays a very stable structure in solution, with the N terminus being back-folded onto the C-terminal α-helix (the so-called PP-fold). The helix of NPY is less stable and the N terminus is freely diffusing in solution. The exchange of this segment, however, does not alter the PP-fold propensities of the chimeric peptides in solution. The structures of the phospholipid micelle-bound peptides serving to mimic the membrane-bound species display segregation into a more flexible N-terminal reg...