Figure 2: The structural model of EGFR tetramers.
From: EGFR oligomerization organizes kinase-active dimers into competent signalling platforms
(a) Key steps in constructing the model of a ligand-bound EGFR tetramer: (1) an initial EGFR dimer model generated using a crystal structure of a HER3 dimer as a template; (2) a face-to-face dimer produced by simulation of the initial dimer model, in which the interaction interface remained unchanged but domains I–III in each monomer departed from the tethered conformation for the conformation seen in the active dimer; (3) domains IV are manually modelled to mimic the conformation of monomers in an active dimer; and (4) a tetramer model constructed by adding two-ligand-bound monomers in back-to-back interactions with the previous dimer. In addition to the ribbons generated using atomic coordinates, cartoon figures are used to illustrate the modeling procedure. (b) The site for the face-to-face interaction (purple) and the outline of the largely overlapping EGF binding site at domains I and III. (c) A diagram illustrating the open-ended oligomerization scheme for EGFR extracellular domains based on repeating the back-to-back and the face-to-face interactions. (d) The full-length structural model of an EGFR tetramer as a dimer of active dimers assembled by the face-to-face interactions. The predicted separation between the N-termini of the two EGF ligands and the average EGF-membrane distance are marked. The coordinates of the model are available in Supplementary Data. (e) The arrangement of the two intracellular active kinase dimers in the tetramer model, by which the phosphorylation site Tyr992 (green) of one receptor is positioned in the proximity of the active site (red) of a kinase domain from the neighbouring dimer.
