MBE Advance Access originally published online on September 17, 2008
Molecular Biology and Evolution 2008 25(12):2643-2652; doi:10.1093/molbev/msn204
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Research Articles |
Evolution of Hormone Signaling in Elasmobranchs by Exploitation of Promiscuous Receptors
Center for Ecology and Evolutionary Biology, University of Oregon
E-mail: joet{at}uoregon.edu.
Accepted for publication September 10, 2008.
Specific interactions among proteins, nucleic acids, and metabolites drive virtually all cellular functions and underlie phenotypic complexity and diversity. Despite the fundamental importance of interactions, the mechanisms and dynamics by which they evolve are poorly understood. Here we describe novel interactions between a lineage-specific hormone and its receptors in elasmobranchs, a subclass of cartilaginous fishes, and infer how these associations evolved using phylogenetic and protein structural analyses. The hormone 1
-hydroxycorticosterone (1-B) is a physiologically important steroid synthesized only in elasmobranchs. We show that 1-B modulates gene expression in vitro by activating two paralogous intracellular transcription factors, the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), in the little skate Leucoraja erinacea; MR serves as a high-sensitivity and GR as a low-sensitivity receptor. Using functional analysis of extant and resurrected ancestral proteins, we show that receptor sensitivity to 1-B evolved millions of years before the hormone itself evolved. The 1-B differs from more ancient corticosteroids only by the addition of a hydroxyl group; the three-dimensional structure of the ancestral receptor shows that the ligand pocket contained ample unoccupied space to accommodate this moiety. Our findings indicate that the interactions between 1-B and elasmobranch GR and MR proteins evolved by molecular exploitation: a novel hormone recruited into new functional partnerships two ancient receptors that had previously interacted with other ligands. The ancestral receptor's promiscuous capacity to fortuitously bind compounds that are slight structural variants of its original ligands set the stage for the evolution of this new interaction.
Key Words: evolution of protein function • evolution of gene networks • hormone receptors • steroid hormones • elasmobranchs • molecular interactions
Douglas Crawford, Associate Editor