Protein dynamics and conformational selection in bidirectional signal transduction

See research article http://www.biomedcentral.com/2046-1682/5/2 webciteCell proliferation, differentiation, migration and adhesion are essential processes in development, morphing cells into critical anatomical structures. When cells approach each other, they may have a seemingly simple choice between adhesion and repulsion; however, the precise positioning of cells, as in the case of vascular patterning or in controlling axon growth in the assembly of topographic neural maps, is highly complex.Orchestrating the subtle signal transduction regulating these events is performed by two membrane-anchored hub protein families: the Eph receptor tyrosine kinases and their ephrin ligands. To accomplish this complicated task, ten EphA and six EphB receptors evolved to interact with six ephrin-A and three ephrin-B ligands, respectively, effectively maximizing the number of combinations of Eph-ephrin interactions while still maintaining specificity, a principle often encountered in evolution.The interactions between the Eph receptors and ephrins of the same subclass are promiscuous; however, cross-subclass binding is observed only for two receptors. EphA3 can bind ephrin-B2, and EphA4 interacts with all nine ephrin ligands, each of which has a different function. Previously, nine EphA4 ligand binding domain (LBD) conformations in complex with the ligands were observed in nine crystal structures. This structural heterogeneity of EphA4 can facilitate cross-subclass ephrin signaling[1]. However, unexpectedly, two new crystal structures of EphA4 revealed eight unique conformations in each crystal structure[2]. These snapshots of multiple conformations of the free EphA4 LDB provide a unique insight into the conformational dynamics of EphA4 and the Eph-ephrin signaling pathways.Based on the loop conformations near the binding site, the newly observed EphA4 LBD structures together with those previously known fall into two groups representing open and closed states, indicating the high