Unraveling the Structural Role of Glycosylation in Regulation of EGFR-ErbB2 Heterodimers

The ErbB/HER protein tyrosine kinase family consist of four members including ErbB1(EGFR), ErbB2, ErbB3 and ErbB4 [1]. EGFR plays a crucial role in several cancers upon its mutation or overexpression [2-4].Ligand binding to the extracellular domain of the ErbB proteins leads to allosteric transition that results in dimerization of the receptors, activation of the protein kinase, trans-autophosphorylation and finally initiation of the signaling cascades in the cytosol [5]. EGFR forms homo and heterodimers with other ErbB family members in order to make an active complex [6].Formation of heterodimers between two different members of the ErbB family, increases the variety of ligands identified by these receptors and signaling pathways that can be activated by a given receptor [7].Glycosylation is covalent binding of sugar moieties to particular amino acids of proteins known as a critical post-translational modification that is involved in activation of EGFR, control and fine-tuning of its interactions[8-10]. We used computational tools to model the heterodimer of EGFR-ErbB2 receptors in the glycosylated and unglycosylated forms. Investigation of the minimized models and hydrogen bonding patterns of the heterodimer shows the plausible role of glycosylation in maintaining a hydrophobic core in the heterodimeric construct.

کلیدواژه ها:

Heterodimer ، EGFR ، ErbB2 ، Glycosylation ، Molecular modeling