An evolutionary perspective on signaling peptides: Toxic peptides are selected to provide information regarding the processing of the propeptide, which represents the phenotypic state of the signaling cell

Structurally similar short peptides often serve as signals in diverse signaling systems. Similar peptides affect diverse physiological pathways in different species or even within the same organism. Assuming that signals provide information, and that this information is tested by the structure of the signal, it is curious that highly similar signaling peptides appear to provide information relevant to very different metabolic processes. Here we suggest a solution to this problem: the synthesis of the propeptide, and its post-translational modifications that are required for its cleavage and the production of the mature peptide, provide information on the phenotypic state of the signaling cell. The mature peptide, due to its chemical properties which render it harmful, serves as a stimulant that forces cells to respond to this information. To support this suggestion, we present cases of signaling peptides in which the sequence and structure of the mature peptide is similar yet provides diverse information. The sequence of the propeptide and its post-translational modifications, which represent the phenotypic state of the signaling cell, determine the quantity and specificity of the information. We also speculate on the evolution of signaling peptides. We hope that this perspective will encourage researchers to reevaluate pathological conditions in which the synthesis of the mature peptide is abnormal.