Peptide hormones depend on reliable recognition by their receptors, based on congruency. If a mutation changes the surface of one of interacting molecules and creates a confined space, a niche, in the otherwise congruent hormone/receptor interface, thiswould allow further mutations confined to the niche space, until one change in molecular shape fills the entire niche space and stops further mutations. Repetition of this process might lead to a different ligand/receptor pair that shows only remote similarities to the initial pair. This paper is aiming to use thismodel of congruency determined coevolution on homophilic membrane molecules to describe evolution of endocrine and paracrine ligands and receptors.
During evolution, a gene of some ancient homophilic membrane molecule with intracellular enzymatic activity might have been duplicated. A new pair of genes (A&B) evolved toward heterophilic binding. Expression of molecules from both genes on neighboring cells might allow congruency-determined coevolution that resulted in heterophilic recognition (A-B and B-A).
Loss of intracellular domains could make one of heterophilic molecules soluble (protoligands) that recognized membrane molecules on other cells (protoreceptors) as a first ligand/receptor pair. New pairs are formed through gene duplication and separate coevolution leading to families of receptors and families of ligands.
Survival pressure forces receptors to remain sensitive and specific, while ligands shrink until they are as small as feasible. Occasionally, plant toxins mimic endogenous peptides (morphine versus endorphins), or receptors can become able to interact with nonpeptide endogenous ligands (steroids, catecholamines). Further receptor evolution congruent to the new ligand can make the initial peptide ligand unrecognizable by that receptor (example: membrane receptors for steroids are without known peptide ligands). Finally, lipid soluble ligands can interact with receptors before receptor molecules reach the cell membrane and are still in the cytoplasm. This can make functional membrane receptors less important (aldosterone, estrogen) or abandoned (other steroids, thyroid hormones)
