Protein Evolution by Molecular Tinkering: Diversification of the Nuclear Receptor Superfamily from a Ligand-Dependent Ancestor

Howard Hughes Medical Institute, Eugene, Oregon, United States of America.
PLoS Biology (Impact Factor: 11.77). 10/2010; 8(10). DOI: 10.1371/journal.pbio.1000497
Source: PubMed

ABSTRACT Author Summary
Many protein families are so diverse that it is hard to determine their ancestral functions and to understand how their derived functions evolved. The existence of so many different functions within protein families often creates the impression that complex, novel functions must have evolved repeatedly and independently. Nuclear receptors (NRs) are a large family of related proteins that regulate key biological processes in animals by binding to specific DNA sequences and triggering expression of nearby target genes. Many NRs are activated by a specific hormone or other small molecule, but some do not require a ligand, and still others are incapable of activating gene expression and so act primarily as repressors of transcription. To understand how the functional diversity of NRs evolved, we reconstructed the structural and functional characteristics of the ancient protein from which the entire family evolved, using genomic, biochemical, functional, and structural analyses in a phylogenetic framework. We show, contrary to current belief, that the ancestral NR was a ligand-activated transcriptional activator that existed in the earliest period of animal evolution. Our analysis reveals how the extraordinary functional diversity of modern receptors was generated by subtle tinkering with this ancestral template—slightly reshaping the ligand cavity, stabilizing the protein's active conformation so it no longer required a ligand, or disabling the protein's capacity to activate transcription without affecting its other properties. We predict that, when sufficient data are gathered to allow detailed evolutionary reconstructions in other protein families, it will become apparent that most protein functional diversity evolved by tinkering with ancient functions; invoking the evolution of wholesale “novelty” will seldom be necessary.

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