Cancer Regulator EGFR‑ErbB4 Heterodimer is Stabilized Through Glycans at the Dimeric Interface

Abstract The ErbB family of tyrosine kinase receptors is composed of four homologous members, including EGFR (ErbB1/HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). Since the ErbB proteins play vital roles in various developmental processes, their mutation or overexpression leads to severe abnormalities such as cancer. The general mechanism of ErbB receptors activity is binding to growth factors via their extracellular domain followed by tyrosine phosphorylation intracellularly. Yet the EGFR and ErbB4 are the only two members that keep their ligand-binding domain and the tyrosine kinase activated. In contrast, ErbB2 and ErbB3 are incapable of keeping their ligand-binding and kinase domains activated, respectively. Active ErbB receptors form homo and heterodimers by binding of two similar or different family members together, respectively. Ligands and intracellular pathways that could be activated through heterodimerization are more diverse compared to homodimers. Moreover, it is known that N-glycosylation is critical for stabilizing and activating the ErbB receptors. In this study, atomistic molecular dynamics simulations were used on one of the most potentiated ErbB heterodimers (EGFR-ErbB4) in the glycosylated and unglycosylated states. It was shown that the EGFR-ErbB4 heterodimer is highly stabilized by glycosylation. The increased stability is most significant at the dimeric interfaces. Regulated by packing of three glycans attached to EGFR (Asn337) and ErbB4 (Asn333, Asn523) at the dimeric interface. Finally, it is proposed that heterodimerization is the persistent key player of the ErbB receptors activation. Thus, targeting the heterodimers in future therapeutic designs could be a promising approach against drug resistance ErbB positive cancers.