A problem with molecular evolution?

[T_aquaticus]

Let’s take a look at a paper which directly addresses the hormone-receptor question in the opening post.

Evolution of hormone-receptor complexity by molecular exploitation - PubMed

Here is the problem. Most vertebrates have two hormone receptors that originated from a gene duplication deep in the vertebrate tree:

mineralocorticoid receptor (MR) : binds to both cortisol and aldosterone, but is associated with aldosterone because it resides in tissue that quickly clears cortisol.

glucocorticoid receptor (GR) : binds to cortisol

So the question is how could aldosterone evolve without a receptor to bind it? Without aldosterone, why would a receptor evolve to bind it?

To answer this question, Bridgham et al. (2006) reconstructed the ancestral protein from before the gene duplication. They could do this because the agnathan branch split off before the gene duplication.

To reconstruct the evolution of the MR’s interaction with aldosterone, we characterized the functions of the ancestral corticoid receptor (AncCR)—the ancient protein from which GR and MR descend by gene duplication. To improve the robustness of this inference, we first isolated corticoid receptor sequences from basal vertebrate taxa. Using the polymerase chain reaction (13), we identified a single corticoid receptor in jawless fishes—the lamprey Petromyzon marinus and the hagfish Myxine glutinosa—and both GR and MR in an elasmobranch, the skate Raja erinacea. Phylogenetic analysis indicates that the duplication leading to GR and MR occurred >450 million years ago, after the diverge
https://science.sciencemag.org/content/312/5770/97.long

So what did they find when they expressed the reconstructed ancestral gene? It was able to bind aldosterone, even though aldosterone had not evolved yet.

We synthesized the AncCR-LBD sequence and expressed it in cultured cells; using a reporter assay, we found that AncCR is a sensitive and effective aldosterone receptor (13). Like the extant CRs and MRs, it is also activated by low doses of DOC and, to a lesser extent, cortisol (Fig. 3A).
https://science.sciencemag.org/content/312/5770/97.long

So just as I said, a new hormone can bind to an already existing hormone receptor that had evolved to bind other hormones. As the paper states:

Using ancestral gene resurrection, we show that, long before the hormone evolved, the receptor’s affinity for aldosterone was present as a structural by-product of its partnership with chemically similar, more ancient ligands.
https://science.sciencemag.org/content/312/5770/97.long