Dynamic equilibrium between multiple active and inactive conformations explains regulation and oncogenic mutations in...

The ErbB growth factor receptor family members are key players in vital physiological and pathological processes. Like other receptor tyrosine kinases, the ErbBs are bi-topic membrane proteins, whose extracellular and intracellular domains are connected by single transmembrane span. In recent years the crystal structures of the extracellular and intracellular domains of some ErbBs have been determined. We integrated the available structural information with phylogenetic, biochemical, biophysical, genetic, and computational data into a suggested model for the regulation and activation of these receptors. According to the model, regulation is maintained by a dynamic equilibrium between monomeric and dimeric states in various conformations. Along this dynamic equilibrium, variations in the points of interactions within the dimers alter the activation state and ligand-binding affinities. The active state was recently shown to be associated with an asymmetric dimer of the kinase domains. That finding enabled us to elucidate, in molecular terms, the directionality observed in the activation process of ErbB heterodimers; it can explain, for example, the preferential activation of ErbB2 by ErbB1 over activation of ErbB1 by ErbB2. Sequence alterations that reverse this directionality lead to aberrant signaling and cancer. Our model also offers molecular interpretations of the effects of various oncogenic alterations that interfere with the regulatory mechanism.