Sci. Signal., 15 September 2009
Structural Biology Not Constitutively Active After All?
Nancy R. Gough
Science Signaling, AAAS, Washington, DC 20005, USA
In humans, the epidermal growth factor receptor (EGFR) family has four members: ErbB1 and ErbB4 are ligand-activated receptor tyrosine kinases, ErbB3 is ligand-binding but catalytically inactive, and ErbB2 is a receptor tyrosine kinase with no known ligand that has been postulated to have ligand-independent activity. The fruitfly Drosophila melanogaster has a single EGFR, the activity of which is controlled by ligand binding. Alvarado et al. crystallized the extracellular domain of dEGFR and compared it to the structures of the human EGFR family and found that the unliganded structure is most similar to ErbB2, the human receptor with presumed constitutive activity. Dimerization is essential for EGFR activation, and structural studies with ErbB1 showed that the extracellular domain of the receptor adopts a "closed" conformation that prevents dimerization and that ligand binding reorients the molecule to expose the dimerization domain. Alvarado et al. found that the dimerization arm in both ErbB2 and dEGFR is exposed in the absence of ligand. Instead of adopting a conformation that "hides" the dimerization arm, these receptors have interactions between domains I and III in the ligand-binding region that position the exposed dimerization domain in such a way that receptor dimerization is prevented. For dEGFR, introducing a ligand into the structure disrupts these interactions, reorienting the dimerization domain. In addition, the unliganded extracellular domain of dEGFR exhibited interactions between domains I and II that contributed to the inactive orientation of the dimerization domain. ErbB2 structures were superimposable on the inactive dEGFR structures, which suggests that the unliganded ErbB2 may be in an inactive conformation. Furthermore, the comparison of dEGFR with the structures of the human EGFR family members suggests that nature has evolved at least two distinct mechanisms for ligand-induced dimerization and activation of EGFRs and that ErbB2 may not be a ligand-independent constitutively active receptor after all. In Drosophila, the strongest EGFR ligands are palmitoylated, and Alvarado et al. suggest that membrane association may also be an important property of the molecules that activate ErbB2, such as the membrane-associated Muc4 subunit.
D. Alvarado, D. E. Klein, M. A. Lemmon, ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature 461, 287–291 (2009). [PubMed]
Citation: N. R. Gough, Not Constitutively Active After All? Sci. Signal. 2, ec304 (2009).
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