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 heterodimers 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 heterodimer 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 heterodimers. 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.

Fig. 1

Variations in C_α-RMSD (A) and radius of gyration, R_g (B) of ER dimer with simulation time. Black line represents ERαβ hetero-dimer while the red line represents ERββ homo-dimer. RMSD matrices of ERαβ hetero-dimer (C) and ERββ homo-dimer (D) computed from MD trajectory.

Fig 2

A. Variations of RMSF profiles of ER homo and hetero-dimer. B. A cartoon representation of ERββ homo-dimer. Regions of high fluctuations are colored in cyan.

Fig 3

Secondary structure evolution with simulation time. A. ERαβ hetero-dimer B. ERββ homo-dimer.

Fig. 4

A. Normalised Eigen value distribution for the first 20 Eigen vectors obtained from MD trajectory. B: 2-D projection of the first two principal components (1 & 2) for ERαβ heterodimer (red) while green represents ERββ dimer.

Fig 5

The essential dimerization interface of ER homo amd hetero dimer interface. Green color represents Chain A and red color represents chain B. Dark green and salmon represents ERββ homo-dimer interface while light green and salmon represent ERαβ hetero-dimer. B. & C. represents electrostatic potential of the dimer interface.

Fig 6

A combined phylogenetic tree for ER alpha and beta across eukaryotic lineages.

Fig. 7

A combined sequence analysis of ERα and ERβ essential dimer interface.