Structural analysis of the evolution of steroid specificity in the mineralocorticoid and glucocorticoid receptors.
BACKGROUND
The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) evolved from a common ancestor. Still not completely understood is how specificity for glucocorticoids (e.g. cortisol) and mineralocorticoids (e.g. aldosterone) evolved in these receptors.


RESULTS
Our analysis of several vertebrate GRs and MRs in the context of 3D structures of human GR and MR indicates that with the exception of skate GR, a cartilaginous fish, there is a deletion in all GRs, at the position corresponding to Ser-949 in human MR. This deletion occurs in a loop before helix 12, which contains the activation function 2 (AF2) domain, which binds coactivator proteins and influences transcriptional activity of steroids. Unexpectedly, we find that His-950 in human MR, which is conserved in the MR in chimpanzee, orangutan and macaque, is glutamine in all teleost and land vertebrate MRs, including New World monkeys and prosimians.


CONCLUSIONS
Evolution of differences in the responses of the GR and MR to corticosteroids involved deletion in the GR of a residue corresponding to Ser-949 in human MR. A mutation corresponding to His-950 in human MR may have been important in physiological changes associated with emergence of Old World monkeys from prosimians.
Baker
Michael E
ME
Department of Medicine, 0693, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, USA. mbaker@ucsd.edu
Chandsawangbhuwana
Charlie
C
Ollikainen
Noah
N
D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D006801:Humans; D008251:Macaca / Q000235:genetics; D009154:Mutation; D002679:Pan troglodytes / Q000235:genetics; D051078:Platyrrhini / Q000235:genetics; D011148:Pongo pygmaeus / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D012694:Serine / Q000235:genetics; D012860:Skates, Fish / Q000235:genetics; D013045:Species Specificity; D011443:Strepsirhini / Q000235:genetics
D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D012694:Serine