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Review
. 2011 Dec;21(6):777-84.
doi: 10.1016/j.sbi.2011.07.007. Epub 2011 Aug 23.

Regulation of the catalytic activity of the EGF receptor

Nicholas F Endres  1 , Kate Engel, Rahul Das, Erika Kovacs, John Kuriyan
Affiliations
Review

Regulation of the catalytic activity of the EGF receptor

Nicholas F Endres et al. Curr Opin Struct Biol. 2011 Dec.

Abstract

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in cell growth that is often misregulated in cancer. Several recent studies highlight the unique structural mechanisms involved in its regulation. Some elucidate the important role that the juxtamembrane segment and the transmembrane helix play in stabilizing the activating asymmetric kinase dimer, and suggest that its activation mechanism is likely to be conserved among the other human EGFR-related receptors. Other studies provide new explanations for two long observed, but poorly understood phenomena, the apparent heterogeneity in ligand binding and the formation of ligand-independent dimers. New insights into the allosteric mechanisms utilized by intracellular regulators of EGFR provide hope that allosteric sites could be used as targets for drug development.

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Conflict of interest statement

Conflict of interest: The authors have no conflict interest…(should we mention pending patent on drug design using asymmetric dimer interface?)

Figures

Figure 1
Figure 1. A simple model for EGFR activation
Activation of EGFR by binding of EGF results in the formation of the asymmetric kinase dimer, and phosphorylation of the C-terminal tail of the receptor. Note that in the absence of ligand EGFR is shown as a monomer, but it ligand-independent dimer may also form [20-24].
Figure 2
Figure 2. Structural model for the activated receptor
Our current structural model for the activated receptor, based on crystal structures of the extracellular and kinase domains [12-14,32,62]. The transmembrane helices and the anti-parallel coiled-coil are modeled based on NMR studies [13,15]. Note that the extracellular domain is extends upon ligand binding stabilizing an extensive dimer interface. This extended conformation provides the proper spacing for the transmembrane domains to dimerize via the N-terminal GxxxG motif, the JM-A region to forms an anti-parallel coiled-coil, and the active asymmetric kinase dimer to be stabilized by the juxtamembrane latch.
Figure 3
Figure 3. Structural model for Negative Cooperativity
The extracellular domain is shown in four possible states observed in published crystal structures of dEGFR [27,28] and human EGFR [6] extracellular domains. Cartoon diagrams below structures depict conformational rearrangements in each state. In the unliganded structure, as observed for dEGFR and Her2 [27], domain I and domain III are collapsed on each other in both molecules of the dimer, occluding the ligand binding site and bending domain II in a way that would weaken dimerization. When one ligand binds as observed in a structure of dEGFR bound to a mutant of Spitz [28], it creates a wedge between domain I and domain III that allows for extensive contact, while the other molecule of the dimer is in a conformation similar to the unbound state. Note that the asymmetric arrangement in this dimer allows for close packing of domain II, stabilizing the dimer interface. A second ligand can bind in this asymmetric dimer in an apparently weaker interaction as seen in the structure of dEGFR bound to Spitz [28], which does not wedge domains I and III apart, but maintains the asymmetry required for the tight dimer interface. When two ligands are tightly bound as seen in the crystal structure of human EGFR bound to EGF [6], the imposed symmetry of the dimer weakens the dimer interface. Figure was adapted from [28].
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