Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family
- D. E. Shaw Research, United States
- Columbia University, United States
Figures
Figure 1
Receptors of the human EGFR family and conformations of their ectodomains.
(A) Left: the four members of the human EGFR family, each consisting of an ectodomain, a single-pass transmembrane helix, and an intracellular module that includes a kinase domain. As shown, Her2 …
Figure 2
Simulations reproduce the gap in the interface of the dEGFR ectodomain dimer.
(A) The schematic shows the 2-ligand dEGFR ectodomain dimer on the left. In simulations initiated from this structure with both ligands removed, gap opened in the dimer interface, as indicated by a …
Figure 3
Bending of domain II.
(A) A schematic showing how the model of the 1-ligand EGFR dimer (right) is generated by simulation after the removal of one EGF ligand from the crystal structure of the 2-ligand dimer (left). The …
Figure 4
Simulations of the EGFR–Her2 heterodimer and the Her2 homodimer.
(A) The EGFR–Her2 heterodimer with the ligand bound to EGFR (‘+EGF’). (B) The ligand-free EGFR–Her2 heterodimer or EGFR–EGFR homodimer (‘−EGF’). (C) The Her2 homodimer. Top: snapshots from the …
Figure 5
Her3–Her2 heterodimer.
(A) Snapshots from the simulations of the Her3–Her2 heterodimer with (left) and without (right) HRG bound to Her3. At the end of the simulation with HRG bound to Her3, HRG was removed, and the …
Figure 6
Details of the dimer interfaces in Her2 heterodimers.
(A) The sequence alignments of EGFR, Her2, Her3, and dEGFR for the part of domain II corresponding to EGFR residues 167–286. Three sets of residues (green, red, and blue, respectively), which are …
Videos
Video 1
The simulation of the ligand-free EGFR–Her2 ectodomain heterodimer with Her2 colored red and EGFR blue. A gap between the N-terminal portion of each subunit’s domain II develops during the simulation.
