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The epidermal growth factor receptor (EGFR) is a tyrosine kinase protein, overexpressed in several cancers. The extracellular domain of EGFR is known to be heavily glycosylated. Growth factor (mostly epidermal growth factor or EGF) binding activates EGFR. This occurs by inducing the transition from the autoinhibited tethered conformation to an extended conformation of the monomeric form of EGFR and by stabilizing the flexible preformed dimer. Activated EGFR adopts a back-to-back dimeric conformation after binding of another homologous receptor to its extracellular domain as the dimeric partner. Several antibodies inhibit EGFR by targeting the growth factor binding site or the dimeric interfaces. Glycosylation has been shown to be important for modulating the stability and function of EGFR. Here, atomistic MD simulations show that N-glycosylation of the EGFR extracellular domain plays critical roles in the binding of growth factors, monoclonal antibodies, and the dimeric partners to the monomeric EGFR extracellular domain. N-glycosylation results in the formation of several noncovalent interactions between the glycans and EGFR extracellular domain near the EGF binding site. This stabilizes the growth factor binding site, resulting in stronger interactions (electrostatic) between the growth factor and EGFR. N-glycosylation also helps maintain the dimeric interface and plays distinct roles in binding of antibodies to spatially separated epitopes of the EGFR extracellular domain. Analysis of SNP data suggests the possibility of altered glycosylation with functional consequences. Proteins 2017; 85:1529-1549. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Interleukin-1 Receptor Type II (IL-1RII) is the decoy receptor of IL-1 cytokines. It down-regulates the immune signalling pathways. There is a competitive behaviour between the IL-1RII and IL-1RI, which is the signalling receptor of the IL-1Rs family. By adopting similarities in structure and specific shared ligands, the two receptors are competing regulators of the immune response. Conformational changes of IL-1RII is a crucial factor in its ligand binding and activation. In addition, dynamics and functionality of the receptor are known to be regulated by glycosylation. Herein, all-atom Molecular Dynamics (MD) simulations were carried out to investigate the dynamics of the apo and cytokine-bound IL-1RII upon full glycosylation. Simulations showed that the IL-1RII presents two extended/active and compact/inactive conformations. Glycosylation maintains the conformation in the extended/active state. Furthermore, It was shown that IL-1 cytokine binding to IL-1RII contributes to stabilisation of the receptor. Comparison of IL-1RI and IL-1RII interaction with IL-1β at the equilibrium condition predicted that glycosylation could increase the binding possibility of IL-1RII towards its ligand. That supports preservation of the active/extended conformation by glycosylation as observed in MD simulations. [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]