The EGFR family tyrosine kinase receptors play fundamental roles in regulating cell proliferation and differentiation. ErbB4, a member of the EGFR family, has been shown to be essential in the development of nervous and cardiovascular systems. Abnormality of the ErbB4 signaling is implied in the pathology of schizophrenia, heart failure and several cancers. Therefore it is of particular interest to study the activation mechanism of this receptor. To initiate the ErbB4 transmembrane signaling, a peptide ligand is called for to shift the monomer-dimer equilibrium of ErbB4 receptor, whereas during this process extracellular region of ErbB4 undergoes a huge conformational change. The interesting part is how exactly this process happens.
Researchers from Shanghai institute of materia medica, DU Yun, YANG Huaiyu and JIANG Hualiang et al., performed one-microsecond (1-μs) molecular dynamics (MD) simulations to understand the mechanism of ErbB4 activation induced by ligand binding. The conformational transition of the ECR-ErbB4/NRG1β complex from an inactive conformation to an active-like form has been observed. The researchers constructed a rough energy landscape for the conformational transition, suggesting that the conformational change from the inactive state to active-like state involves a stable conformation. The energy barrier for the tether opening was estimated as ~2.7 kcal/mol, which is very close to the experimental value reported for ErbB1. Based on the simulation results, an atomic mechanism for the ligand-induced activation of ErbB4 was postulated. The study provides clues for studying the activation mechanism of other ErbBs and for designing new therapies targeting these receptors.
The results has been published on Journal of the American Chemical Story (2012, 134:6720-6731) and selected as the cover story. The study was supported by NSFC and 973.