title: Interactions of the EGFR juxtamembrane domain with PIP2-containing lipid bilayers: Insights from multiscale molecular dynamics simulations.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Khairul Bariyyah
authors.initials: KB
authors.lastname: Abd Halim
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Heidi
authors.initials: H
authors.lastname: Koldsø
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: mark.sansom@bioch.ox.ac.uk.
authors.forename: Mark S P
authors.initials: MSP
authors.lastname: Sansom
mesh_terms: D004789:Enzyme Activation; D004795:Enzyme Stability; D066246:ErbB Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D008051:Lipid Bilayers; D019269:Phosphatidylinositol 4,5-Diphosphate; D066246:ErbB Receptors
keywords: EGFR; Juxtamembrane domain; Lipid bilayer; Molecular dynamics; PIP(2)