Resurrecting the Ancestral Steroid Receptor: Ancient Origin of Estrogen Signaling

Abstract

Two datasets, the geologic record and the genetic content of extant organisms, provide complementary insights into the history of how key molecular components have shaped or driven global environmental and macroevolutionary trends. Changes in global physicochemical modes over time are thought to be a consistent feature of this relationship between Earth and life, as life is thought to have been optimizing protein functions for the entirety of its ~3.8 billion years of history on Earth. Organismal survival depends on how well critical genetic and metabolic components can adapt to their environments, reflecting an ability to optimize efficiently to changing conditions. The geologic record provides an array of biologically independent indicators of macroscale atmospheric and oceanic composition, but provides little in the way of the exact behavior of the molecular components that influenced the compositions of these reservoirs. By reconstructing sequences of proteins that might have been present in ancient organisms, we can identify a subset of possible sequences that may have been optimized to these ancient environmental conditions. How can extant life be used to reconstruct ancestral phenotypes? Configurations of ancient sequences can be inferred from the diversity of extant sequences, and then resurrected in the lab to ascertain their biochemical attributes. One way to augment sequence-based, single-gene methods to obtain a richer and more reliable picture of the deep past, is to resurrect inferred ancestral protein sequences in living organisms, where their phenotypes can be exposed in a complex molecular-systems context, and to then link consequences of those phenotypes to biosignatures that were preserved in the independent historical repository of the geological record. As a first-step beyond single molecule reconstruction to the study of functional molecular systems, we present here the ancestral sequence reconstruction of the beta-carbonic anhydrase protein. We assess how carbonic anhydrase proteins meet our selection criteria for reconstructing ancient biosignatures in the lab, which we term paleophenotype reconstruction.

Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

“…ERRs are still not fully understood [9,15,16,19,21] Trichoplax, which is considered to be the simplest metazoan [28,29] and of three lophotrochozoans: Capitella, a segmented worm, Helobdella, a leech and Lottia, a snail.…”

“…Similar to ERRs, invertebrate ERs do not bind estradiol with high affinity, in contrast to vertebrate ERs, which are activated by 0.2 nM estradiol [24]. Also, similar to ERRs, invertebrate ERs are constitutively active transcription factors in cell assays [19,21,22]. A biological function for invertebrate ERs has not been reported.…”

“…Complicating understanding the evolution of ERRs and vertebrate ERs was the cloning in the last five years of several invertebrate ERs from mollusks [19][20][21][22][23]. Invertebrate ERs have about 35% sequence identity and 55% positive matches with the estrogen-binding domain in human ERα.…”

Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

“…[8][9][12][13][14]. Although mollusks and annelids contain receptors with sequence similarity to the human ER [15][16][17], there is disagreement as to whether these protostome receptors diverged from a common ancestor of chordate ER [17], or if the similarity between protostome proteins and the chordate ER is an example of convergent evolution [18][19][20]. The pros and cons of this controversy are discussed in [17][18][19][20] and are not the focus of this paper.…”

3D model of amphioxus steroid receptor complexed with estradiol

“…To investigate the basis for these unexpected properties of amphioxus SR and to begin to understand early events in the evolution steroid receptors [4,6,7,9,13,14,[16][17][18], we constructed a 3D model of amphioxus SR complexed with estradiol. Our 3D model predicts a novel structure in the steroid-binding domain of the SR.…”