Ectodomain orientation, conformational plasticity and oligomerization of ErbB1 receptors investigated by molecular dynamics.
Epidermal growth factor receptor (EGFR; ErbB1, HER1 in humans) is a receptor tyrosine kinase triggering signals across the plasma membranes of cells to determine cell fate. We have used molecular dynamics simulations to investigate structural models of ErbB1 ectodomains. We show that, with minor rearrangements, the ErbB1 back-to-back dimer can align almost flat on the cell membrane. This is in contrast to the traditional picture of ErbB1 dimers standing proud of the membrane, but in line with recent FRET and EM experiments. Interaction with the membrane leads to conformational changes in the dimer, which further stabilize the back-to-back interface. On the membrane, two dimers can associate forming a tetramer. This is enabled by a head-to-head interface, involving the ligand binding side of the ectodomain, and which significantly enhances ligand binding. A weak head-to-head interface has been seen in crystal structures, but is found to stabilise appreciably in our simulation. We also find that the domains IV, connecting the receptor to the membrane, weakly interact with each other. These simulations illustrate some of the flexibility of the ErbB1 ectodomains, and may help to explain recent experimental results.
Kästner
Johannes
J
Computational Science and Engineering Department, STFC Daresbury Laboratory, Warrington, UK.
Loeffler
Hannes H
HH
Roberts
Selene K
SK
Martin-Fernandez
Marisa L
ML
Winn
Martyn D
MD
D000818:Animals; D002462:Cell Membrane; D003198:Computer Simulation; D066246:ErbB Receptors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D018583:Pliability; D011487:Protein Conformation; D055503:Protein Multimerization
D008024:Ligands; D008565:Membrane Proteins; D066246:ErbB Receptors