Insight into estrogen receptor beta–beta and alpha–beta homo- and heterodimerization: A combined molecular dynamics and sequence analysis study

Abstract

Biological effects of estrogenic ligands are transduced by two estrogen receptors, ERα and ERβ; they transactivate as dimers. Since ERββ and ERαβ homo and hetero dimers are known to exhibit anti-proliferative effects, we characterized their dimerization interface in atomic details and explored their ligand induced conformational dynamics. ERαβ heterodimer is found to be relatively more stable than the ERββ homodimer and the observed differences are mainly due to loop dynamics. The principal component analysis reveals that, in the essential subspace, the homo and hetero dimer dynamics are distinctively different. The core recognition groove of the dimer interface, formed by helix 9 and helix 10/11, remains unaltered in both homo and hetero dimers. The dimerization surfaces are found to be highly conserved in eukaryotic lineages. Phylogenetic patterns for ERα appear to be very much similar to that of ERβ which signifies that the formation of functional heterodimer is evolutionary selected.

G protein‐coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain

“…The possibility of a cross talk between ERs should always be taken into consideration. 41 We observed slightly different effects in vitro and in vivo, indicating functional plasticity of classical and novel ERs.…”

The Role of Estrogen Receptor β in Prostate Cancer

“…ERβ/β and ERα/β homo-and hetero dimers, respectively, exhibit antiproliferative effects as they activate different target genes (11). Interestingly, ERα/β heterodimer is more stable than the ERβ/β homodimer (12). Overall, ER dimerization is a crucial step in defining ER signaling (11).…”

Structural and functional characteristics of oestrogen receptor β splice variants: Implications for the ageing brain

“…In both humans and rats, the DNA‐binding domains (DBD) of ERα and ERβ show over 95% sequence homology. Therefore, it is not surprising that ERα and ERβ can form functional heterodimers, and recent in silico modelling demonstrated that the heterodimer is more stable than the ERβ homodimer …”

“…Therefore, it is not surprising that ERα and ERβ can form functional heterodimers, 34 and recent in silico modelling demonstrated that the heterodimer is more stable than the ERβ homodimer. 35 The D domain is a flexible hinge region that provides a functional link between the DBD and the LBD. This region harbours the nuclear localisation signal, which, upon ligand binding, allows the receptor to translocate from the cytoplasm to the nucleus where it can interact with DNA.…”