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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]

Epidermal Growth Factor Receptor (EGFR) is a glycosylated tyrosine kinase receptor associated with several cancers. EGFR plays an important role in cancer therapy and inspired several experimental and computational (molecular dynamics simulation) studies to investigate its function and dynamics. N-glycosylation is a critical aspect of EGFR functioning that was mainly unexplained until recently due to the challenges in obtaining and analysis of the structural data involving the glycan moieties. Latest simulations of glycosylated EGFR suggest atomistic mechanisms underlying the experimentally proposed functions of N-glycans in: EGFR increased ligand binding, reduced flexibility and arrangement within the cell membrane. It was shown that the increase in the ligand binding of glycosylated EGFR is mediated by the interaction between the two glycans attached to the growth factor binding subdomains resulting in stabilization of the growth factor binding site. Persistent hydrogen bonds’ formation between the glycans and EGFR contributes to proper folding and reduced flexibly of the glycosylated receptor. Assembly of the cell-integrated EGFR and its relative distance from the membrane are acquired by the lift-up action of the attached glycans. These findings can be used as a framework for implementation of computational techniques to obtain atomistic details of protein glycosylation as one of the most important areas of structural biology. [ABSTRACT FROM AUTHOR]

Epidermal Growth Factor Receptor (EGFR) is a glycosylated tyrosine kinase receptor associated with several cancers. EGFR plays an important role in cancer therapy and inspired several experimental and computational (molecular dynamics simulation) studies to investigate its function and dynamics. N-glycosylation is a critical aspect of EGFR functioning that was mainly unexplained until recently due to the challenges in obtaining and analysis of the structural data involving the glycan moieties. Latest simulations of glycosylated EGFR suggest atomistic mechanisms underlying the experimentally proposed functions of N-glycans in: EGFR increased ligand binding, reduced flexibility and arrangement within the cell membrane. It was shown that the increase in the ligand binding of glycosylated EGFR is mediated by the interaction between the two glycans attached to the growth factor binding subdomains resulting in stabilization of the growth factor binding site. Persistent hydrogen bonds’ formation between the glycans and EGFR contributes to proper folding and reduced flexibly of the glycosylated receptor. Assembly of the cell-integrated EGFR and its relative distance from the membrane are acquired by the lift-up action of the attached glycans. These findings can be used as a framework for implementation of computational techniques to obtain atomistic details of protein glycosylation as one of the most important areas of structural biology. [ABSTRACT FROM AUTHOR]