Interactions of the EGFR juxtamembrane domain with PIP2-containing lipid bilayers: Insights from multiscale molecular dynamics simulations

• Published in: Biochimica et biophysica acta Vol. 1850; no. 5; pp. 1017 - 1025
• Main Authors: Abd Halim, Khairul Bariyyah, Koldsø, Heidi, Sansom, Mark S.P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2015; Elsevier Pub. Co
• Subjects: deformation; EGFR; Enzyme Activation; Enzyme Stability; epidermal growth factor receptors; Juxtamembrane domain; Lipid bilayer; lipid bilayers; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; lipids; mammals; Molecular dynamics; Molecular Dynamics Simulation; Mutation; Phosphatidylinositol 4,5-Diphosphate - chemistry; Phosphatidylinositol 4,5-Diphosphate - metabolism; PIP2; Protein Binding; Protein Multimerization; Protein Structure, Tertiary; Receptor, Epidermal Growth Factor - chemistry; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Structure-Activity Relationship; Molecular dynamics; Lipid bilayer; Juxtamembrane domain; EGFR; PIP2; PIP
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.09.006

The epidermal growth factor receptor (EGFR) is the best characterised member of the receptor tyrosine kinases, which play an important role in signalling across mammalian cell membranes. The EGFR juxtamembrane (JM) domain is involved in the mechanism of activation of the receptor, interacting with the anionic lipid phosphatidylinositol 4,5-bisphosphate (PIP2) in the intracellular leaflet of the cell membrane. Multiscale MD simulations were used to characterize PIP2–JM interactions. Simulations of the transmembrane helix plus JM region (TM–JM) dimer (PDB:2M20) in both PIP2-containing and PIP2-depleted lipid bilayer membranes revealed the interactions of the JM with PIP2 and other lipids. PIP2 forms strong interactions with the basic residues in the R645–R647 motif of the JM domain resulting in clustering of PIP2 around the protein. This association of PIP2 and the JM domain aids stabilization of JM-A dimer away from the membrane. Mutation (R645N/R646N/R647N) or PIP2-depletion results in deformation of the JM-A dimer and changes in JM–membrane interactions. These simulations support the proposal that the positively charged residues at the start of the JM-A domain stabilize the JM-A helices in an orientation away from the membrane surface through binding to PIP2, thus promoting a conformation corresponding to an asymmetric (i.e. activated) kinase. This study indicates that MD simulations may be used to characterise JM/lipid interactions, thus helping to define their role in the mechanisms of receptor tyrosine kinases. This article is part of a Special Issue entitled Recent developments of molecular dynamics. •EGFR transmembrane–juxtamembrane dimer was simulated in PIP2-containing bilayers.•PIP2 forms favourable interactions with basic residues of the JM region.•Mutation or PIP2 depletion changes juxtamembrane interactions with the bilayer.•Simulations support interactions with anionic lipids in activation of the EGFR.