Prohormonal cleavage sites are associated with omega loops

Secretory peptides are generated from larger precursor proteins, or prohormones, by proteolytic cleavage at sites consisting of one or more basic amino acids. We have investigated the association of these cleavage sites with the various classes of secondary structure in the prohormones. In particular, we determined the association of cleavage sites with the newly defined category of omega loops. We developed an algorithm for predicting the occurrence of such loops from the primary structure of the precursor and validated this procedure by comparison to crystallographic data. When this method was applied to prohormones, we found that about one-third of the cleavage sites previously assigned to reverse turns were actually associated with omega loops. Moreover, sites that delimit secreted peptides are most often associated with loops and are concentrated in the neck regions of the loops. These data are interpreted in terms of a model in which the processing endoprotease interacts with two sites on the prohormone: a recognition site in the middle of a loop and the cleavage site at its neck.