Cancer regulator EGFR-ErbB4 heterodimer is stabilized through glycans at the dimeric interface.

EGFR and ErbB4 are the only two members of cancer-regulating ErbB RTKs that maintain the activation of their extracellular ligand-binding domain and intracellular tyrosine kinase domain. EGFR and ErbB4 could form homo and heterodimers upon their activation. Heterodimerization triggers more diverse intracellular pathways compared to homodimerization. Moreover, it is known that N-glycosylation is crucial for the stabilization and activation of EGFR and ErbB4 receptors. Herein, atomistic molecular dynamics were simulated to study the EGFR-ErbB4 heterodimer 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 in the EGFR and ErbB4 activation. Thus, targeting the heterodimers in future therapeutic designs could be a promising approach against drug resistance to ErbB-positive cancers. [ABSTRACT FROM AUTHOR]