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Molecular and Cellular Biology, September 2005, p. 7734-7742, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7734-7742.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Epidermal Growth Factor Receptor Dimerization and Activation Require Ligand-Induced Conformational Changes in the Dimer Interface

Jessica P. Dawson,^1, Mitchell B. Berger,^1, Chun-Chi Lin,² Joseph Schlessinger,³ Mark A. Lemmon,^1* and Kathryn M. Ferguson²

Department of Biochemistry and Biophysics,¹ Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,² Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut³

Received 24 January 2005/ Returned for modification 17 March 2005/ Accepted 13 June 2005

Structural studies have shown that ligand-induced epidermal growth factor receptor (EGFR) dimerization involves major domain rearrangements that expose a critical dimerization arm. However, simply exposing this arm is not sufficient for receptor dimerization, suggesting that additional ligand-induced dimer contacts are required. To map these contributions to the dimer interface, we individually mutated each contact suggested by crystallographic studies and analyzed the effects on receptor dimerization, activation, and ligand binding. We find that domain II contributes >90% of the driving energy for dimerization of the extracellular region, with domain IV adding little. Within domain II, the dimerization arm forms much of the dimer interface, as expected. However, a loop from the sixth disulfide-bonded module (immediately C-terminal to the dimerization arm) also makes a critical contribution. Specific ligand-induced conformational changes in domain II are required for this loop to contribute to receptor dimerization, and we identify a set of ligand-induced intramolecular interactions that appear to be important in driving these changes, effectively "buttressing" the dimer interface. Our data also suggest that similar conformational changes may determine the specificity of ErbB receptor homo- versus heterodimerization.

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* Corresponding author. Mailing address: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104-6059. Phone: (215) 898-3072. Fax: (215) 573-4764. E-mail: mlemmon{at}mail.med.upenn.edu.

J.P.D. and M.B.B. contributed equally to this study.

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Molecular and Cellular Biology, September 2005, p. 7734-7742, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7734-7742.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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