N-terminal domain Increases Activation of Elephant Shark Glucocorticoid and Mineralocorticoid Receptors

TL;DR

This study reveals that the N-terminal domain of elephant shark glucocorticoid receptor enhances its activation by corticosteroids, providing insights into the early evolution of steroid hormone receptor function.

Contribution

It demonstrates that the N-terminal domain significantly increases activation of elephant shark GR, highlighting an evolutionary step in GR divergence from MR.

Findings

N-terminal domain boosts corticosteroid activation of elephant shark GR

Deletion of NTD reduces GR response to corticosteroids

Chimeric receptors show NTD's role in receptor activation

Abstract

Cortisol, corticosterone and aldosterone activate full-length glucocorticoid receptor (GR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Activation by aldosterone a mineralocorticoid, indicates partial divergence of elephant shark GR from the MR. Progesterone activates elephant shark MR, but not elephant shark GR. Progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Deletion of the N-terminal domain (NTD) from elephant shark GR (Truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Chimeras of elephant shark GR NTD fused to MR DBD+LBD had increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length elephant shark MR, indicating that activation of human GR by the NTD evolved early in GR divergence from the MR.