Promiscuous and specific recognition among ephrins and Eph receptors

Abstract

Eph-ephrin interactions control the signal transduction between cells and play an important role in carcinogenesis and other diseases. The interactions between Eph receptors and ephrins of the same subclass are promiscuous; there are cross-interactions between some subclasses, but not all. To understand how Eph-ephrin interactions can be both promiscuous and specific, we investigated sixteen energy landscapes of four Eph receptors (A2, A4, B2, and B4) interacting with four ephrin ligands (A1, A2, A5, and B2). We generated conformational ensembles and recognition energy landscapes starting from separated Eph and ephrin molecules and proceeding up to the formation of Eph-ephrin complexes. Analysis of the Eph-Ephrin recognition trajectories and the co-evolution entropy of 400 ligand binding domains of Eph receptor and 241 ephrin ligands identified conserved residues during the recognition process. Our study correctly predicted the promiscuity and specificity of the interactions and provided insights into their recognition. The dynamic conformational changes during Eph-ephrin recognition can be described by progressive conformational selection and population shift events, with two dynamic salt bridges between EphB4 and Ephrin-B2 contributing to the specific recognition. EphA3 cancer-related mutations lowered the binding energies. The specificity is not only controlled by the final stage of the interaction across the protein-protein interface, but also has large contributions from binding kinetics with the help of dynamic intermediates along the pathway from the separated Eph and ephrin to the Eph-ephrin complex.

Antigen binding allosterically promotes Fc receptor recognition

“…37,38 Conformational dynamics permits both promiscuity and specificity. 34,[39][40][41][42][43][44] Protein complex formation redistributes the dynamics, 45,46 allowing allosteric signaling through protein domains. Antibody-antigen recognition, which is associated with structural transitions through inherent conformational flexibility, [5][6][7] involves conformational selection.…”

Eph receptor signalling: from catalytic to non-catalytic functions

“…Human EphA receptors (EphA1-A8 and EphA10) preferentially bind to the ephrin A ligands, whereas human EphB receptors (EphB1-B4 and EphB6) bind to the ephrin B ligands. However, promiscuous binding of EphA receptors to ephrin-Bs, or EphB receptors to ephrin-As have been shown [5][6][7]. The specificity of the Eph receptors appears to be dictated by their ectodomains, as shown in a chimera experiment [8].…”

Optogenetic activation of EphB2 receptor in dendrites induced actin polymerization by activating Arg kinase

“…The 14 known members of the Eph receptor family are further divided into two subfamilies: the nine EphA (A1-A8, A10) receptors which primarily bind to GPI (glycosyl phosphatidylinositol)-linked ephrin-A ligands, and the five EphB (B1-B4, B6) receptors which primarily bind to transmembrane ephrin-B ligands ( Janes et al, 2012 ; Sloniowski and Ethell, 2012 ). Despite these ligand preferences, multiple studies have shown that cross-subfamily binding is also possible and the Eph receptors' ligand specificities are not absolute ( Kullander and Klein, 2002 ; Himanen et al, 2004 ; Noberini et al, 2012 ; Dai et al, 2014 ). Nevertheless, in most physiologic cases, both the receptors and their ligands are membrane-bound.…”