Editors' ChoiceReceptors

ErbB Family Interactions

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Science's STKE  04 Mar 2003:
Vol. 2003, Issue 172, pp. tw94-TW94
DOI: 10.1126/stke.2003.172.tw94

The ErbB family of receptor tyrosine kinases, which mediates the response to epidermal growth factor (EGF) and related peptides, contains four members: the EGF receptor (EGFR, ErbB1), ErbB2, ErbB3, and ErbB4. EGFR, ErbB3, and ErbB4 undergo ligand-dependent homo- or heterodimerization, which, together with their sensitivity to multiple ligands, confers complexity on ErbB signaling. ErbB2, which does not bind ligand, is the preferred partner for the others, but forms homodimers only when mutated or overexpressed, conditions associated with human malignancies. Building on recent research describing the structure of ligand-bound dimers of EGFR extracellular regions, two groups investigated the mechanisms whereby EGF stimulates EGFR dimerization and by which ligand-free ErbB2 dimerizes with other ErbB receptors. Ferguson et al. determined the 2.8 Å resolution crystal structure of the inactive monomeric EGFR extracellular domain (sEGFR), revealing a conformation in which a region required for dimerization was buried by intramolecular interactions. Mutations disrupting this interaction increased EGF binding affinity. The authors developed a model in which unliganded sEGFR exists in an equilibrium between a clasped conformation, which is incompatible with EGF binding and dimerization, and an extended configuration that allows dimerization and is stabilized by ligand binding. EGF binds to a fraction of sEGFRs already in the extended form, driving the equilibrium toward the dimerization-competent form. Garrett et al. determined the 2.5 Å resolution structure of a truncated ErbB2 extracellular domain, revealing a conformation similar to that of the ligand-bound EGFR, which was thus ready to form heterodimers with other ErbB receptors. Regions corresponding to EGFR ligand-binding domains were occluded, making EGF binding impossible, and electrostatic repulsion appeared likely to inhibit homodimerization.

K. M. Ferguson, M. B. Berger, J. M. Mendrola, H.-S. Cho, D. J. Leahy, M. A. Lemmon, EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Molecular Cell 11, 507-517 (2003). [Online Journal]

T. P. J. Garrett, N. M. McKern, M. Lou, T. C. Elleman, T. E. Adams, G. O. Lovrecz, M. Kofler, R. N. Jorissen, E. C. Nice, A. W. Burgess, C. W. Ward, The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Molecular Cell 11, 499-505 (2003). [Online Journal]

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