Estrogen receptor alpha—Identification by a modeling approach of a potential polyproline II recognizing domain within the AF-2 region of the receptor that would play a role of prime importance in its mechanism of action

Abstract

Estrogen receptors (ERs) behave not only as ligand-dependent transcriptional factors; they can also trigger non-genomic responses involving mitogen activated protein kinases (MAPKs), reported to be crucial in transduction cascades. MAPKs are partially activated by proteins with domains able to interact with polyproline II (PPII) regions. Recent studies have brought up the direct interaction of PPII-containing proteins with the α subtype human ER (ERα). Such observations suggest that ERα may contain a “PPII recognizing domain” (PRD). By sequence alignment, we identified such a potential PRD within the AF-2 region of ERα (residues 351–414). According to our modeling studies based on X-ray structural data, this PRD appears to be divided in two sub-regions known to interact with α-helix containing coactivators. Our data also reveal the potential existence of intramolecular interactions of this domain with a large PPII-rich region of the receptor (residues 301–330). Implication of these regulatory structural elements in both genomic and non-genomic responses seems likely.