Protein dynamics and conformational selection in bidirectional signal transduction

Abstract

Protein conformational dynamics simultaneously allow promiscuity and specificity in binding. The multiple conformations of the free EphA4 ligand-binding domain observed in two new EphA4 crystal structures provide a unique insight into the conformational dynamics of EphA4 and its signaling pathways. The heterogeneous ensemble and loop dynamics explain how the EphA4 receptor is able to bind multiple A- and B-ephrin ligands and small molecules via conformational selection, which helps to fine-tune cellular signal response in both receptor and ligand cells.

Figure 1

The populations are dynamic and are affected by various factors, including binding. Ligand binding could allosterically affect a second binding site. Because different ligands can allosterically lead to different (second site) conformations and these sites can then select other partners, the effects can propagate downstream through altered signal transduction pathways. (a) A high energy barrier may separate the open and closed conformations, as observed for the Eph receptor[2] Sixteen Eph receptor conformations co-exist in two crystals, with eight in each asymmetric unit. Eleven of these can be classified as closed conformations, and five as open. (b) Different conformations of the protein can bind multiple ligands via conformational selection. Protein conformational change at one site (BS1) is cooperatively coupled with a change in another site (BS2), in the same or another domain. The conformational selection in BS1 can be coupled with the conformational changes in the BS2. In turn, these conformational changes in BS2 can influence signal transduction pathways through subsequent binding events. The open and closed Eph conformations are taken from Figure 2b,c in [2], with permission from BMC Biophysics

Figure 2

Because both ephrins and Eph receptors have multiple binding sites, however, Eph-ephrin binding may further form hetero-tetramer or higher oligomers if tighter cell-cell adhesion is required [11]. The figure shows the dimeric and tetrameric complexes observed in the crystal structure (PDB: 1KGY).