Reduced steroid activation of elephant shark glucocorticoid and mineralocorticoid receptors after inserting four amino acids from the DNA-binding domain of lamprey corticoid receptor-1

TL;DR

This study investigates how inserting four amino acids into elephant shark steroid receptors' DNA-binding domains reduces their activation by corticosteroids, shedding light on receptor evolution and function.

Contribution

The paper demonstrates that adding four amino acids from lamprey CR1 into elephant shark MR and GR decreases their steroid-induced transcriptional activation, revealing evolutionary functional changes.

Findings

Insertion of four amino acids reduces steroid activation of MR and GR.

Wild-type elephant shark receptors lack these amino acids, leading to higher activation.

Evolutionary analysis suggests these amino acids modulate receptor sensitivity.

Abstract

Atlantic sea lamprey contains two corticoid receptors (CRs), CR1 and CR2, that are identical except for a four amino acid insert (Thr-Arg-Gln-Gly) in the CR1 DNA-binding domain (DBD). Steroids are stronger transcriptional activators of CR2 than of CR1 suggesting that the insert reduces the transcriptional response of lamprey CR1 to steroids. The DBD in elephant shark mineralocorticoid receptor (MR) and glucocorticoid receptor (GR), which are descended from a CR, lack these four amino acids, suggesting that a CR2 is their common ancestor. To determine if, similar to lamprey CR1, the presence of this insert in elephant shark MR and GR decreases transcriptional activation by corticosteroids, we inserted these four CR1-specific residues into the DBD of elephant shark MR and GR. Compared to steroid activation of wild-type elephant shark MR and GR, cortisol, corticosterone, aldosterone, 11-deoxycorticosterone and 11-deoxycortisol had lower transcriptional activation of these mutant MR and GR receptors, indicating that the absence of this four-residue segment in the DBD in wild-type elephant shark MR and GR increases transcriptional activation by corticosteroids.