Resurrection of 450 million year old protein illustrates how an integrated system evolved in a stepwise fashion
By Charles Choi | April 7, 2006
An ancient receptor appears sensitive to the same hormone that activates its modern descendant, providing clues to how a lock-and-key relationship evolved between a hormone and its far older receptor, according to this week'sScience. These findings illustrate the means by which complex, tightly integrated parts could have evolved in a stepwise, Darwinian fashion.
To obtain their findings, the researchers used phylogenic analyses to ?resurrect? a 450 million year old protein and determine the process that led it to its current form. "It's almost as though they had a time machine to go back and look at the ancient interactions," Richard Lenski at Michigan State University, who did not participate in this study, told The Scientist.
The researchers, headed by Joseph Thornton at the University of Oregon in Eugene, focused on the history of the relationship between the steroid hormone aldosterone, currently only seen in tetrapods, and the mineralocorticoid receptor, which emerged some 75 million years before its partner.
Using polymerase chain reaction (PCR) analysis, they identified a corticoid receptor in two jawless fishes, and the mineralocorticoid receptor and glucocorticoid receptor in a cartilaginous fish. Phylogenetic analysis indicated a gene duplication event of an ancestral corticoid receptor gave rise to both the mineralocorticoid receptor and the glucocorticoid receptor more than 450 million years ago, after jawless fishes diverged but before cartilaginous fish split from bony vertebrates.
Further analyses revealed that the jawless and cartilaginous fish receptors are activated by very low doses of aldosterone, cortisol, and 11-deoxycorticosterone (DOC), but the glucocorticoid receptors of bony vertebrates were insensitive to aldosterone. This suggested the ancestral corticoid receptor could have been activated by aldosterone, but that sensitivity to aldosterone disappeared in the glucocorticoid receptors of bony vertebrates.
The researchers then reconstructed the likely amino acid sequence of the ancestral corticoid receptor's ligand-binding domain using phylogeny and existing receptor sequences, and expressed the putative ancient receptor in cultured Chinese hamster ovary cells. They found that the reconstructed ancestral corticoid receptor is a sensitive and effective aldosterone receptor.
The researchers suggest that the ancestral receptor?s response to aldosterone stemmed from its affinity for ancient ligands chemically similar to aldosterone, such as DOC, which differs from aldosterone by small moeities at only two positions. Subsequent analyses suggested that substitutions of only two amino acid sequences caused the glucocorticoid to lose its sensitivity to aldosterone.
"My assumption would have been that, as with androgen receptor and progesterone receptor, the steroid came first and that the ancestral receptor gradually evolved," Scott MacKenzie at the University of Glasgow in Scotland, who did not participate in this study, told The Scientist. He felt Thornton and colleagues "argued persuasively" for a "receptor-first" scenario.
Nicolette Farman at the College of France in Paris, also not a co-author, told The Scientist she found the work "fascinating," and that future research could examine the evolution of the enzyme that metabolizes glucocorticoids to prevent them from inadvertently binding to the mineralocorticoid receptor. "It'd be nice to know when and where the enzyme evolved, which could help explore what role the ancestral corticoid receptor played and changed over time."
Biological systems composed of highly integrated parts are a rallying cry for the intelligent design movement, which claims them as examples of so-called irreducible complexity that could not have formed in a stepwise manner under natural selection. "While I would say our work reveals a fundamental logical flaw in the irreducible complexity argument, that's not what motivated us. Questions of evolutionary biology did," study author Thornton told The Scientist. He and his colleagues next plan to examine other steroid hormone and receptor systems, such as those of estrogen and testosterone.
Links within this article
J.T. Bridgham et al. "Evolution of hormone-receptor complexity by molecular exploitation," Science, April 7, 2006.
K.Y. Kreeger. "Six scientists are added to ranks of prestigious MacArthur fellows," The Scientist, September 2, 1996
M. Greener. "Steroid action gets a rewrite," The Scientist, September 8, 2003.
D. Bruce, "Walking from water," The Scientist, July 4, 2002
N.S. Greenspan. "Not-so-intelligent design," The Scientist, March 4, 2002.
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