Glycosylation Affects the Conformational Behavior of EGFR

Abstract

Glycosylation where glycans are enzymatically attached to proteins is a common post-translational modification among many membrane protein families. The glycans associated with glycosylation serve a variety of structural and functional roles in protein structures, such as recognition and cell-cell adhesion. Determination of glycosylation in membrane protein structures is a complicated matter, though, since due to methodological limitations and the soft nature of glycans, the structure of the crystallized membrane proteins does not include the information arising from glycosylation. Here we use extensive atomistic molecular dynamics simulations together with experimental ligand binding assays and antibodies (1) to show for the N-glycosylated human epidermal growth factor receptor (EGFR) in biomimetic lipid bilayers that N-glycosylation is a crucial determinant of EGFR conformation, and specifically the orientation of the EGFR ectodomain relative to the membrane. It is expected that similar conclusions as to the importance of glycosylation in protein conformational behavior can be drawn for a number of other membrane proteins, too.(1) K. Kaszuba et al., Proc. Natl. Acad. Sci. USA 112, 4334 (2015).