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

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Published inMolecular and Cellular Biology Vol. 25; no. 17; pp. 7734 - 7742
Main Authors Dawson, Jessica P., Berger, Mitchell B., Lin, Chun-Chi, Schlessinger, Joseph, Lemmon, Mark A., Ferguson, Kathryn M.
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 01.09.2005
Taylor & Francis
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Abstract Article Usage Stats Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to MCB .asm.org, visit: MCB       
AbstractList 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.
Article Usage Stats Services MCB Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue MCB About MCB Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy MCB RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0270-7306 Online ISSN: 1098-5549 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to MCB .asm.org, visit: MCB       
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.
Author Jessica P. Dawson
Chun-Chi Lin
Mitchell B. Berger
Mark A. Lemmon
Kathryn M. Ferguson
Joseph Schlessinger
AuthorAffiliation 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, Connecticut 3
AuthorAffiliation_xml – name: 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, Connecticut 3
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  surname: Dawson
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  surname: Ferguson
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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@mail.med.upenn.edu.
J.P.D. and M.B.B. contributed equally to this study.
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Structural studies have shown that ligand-induced epidermal growth factor receptor (EGFR) dimerization involves major domain rearrangements that expose a...
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StartPage 7734
SubjectTerms Binding Sites
Dimerization
Enzyme Activation
Ligands
Models, Molecular
Molecular Sequence Data
Mutation - genetics
Protein Structure, Quaternary
Protein Structure, Tertiary
Receptor, Epidermal Growth Factor - chemistry
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - metabolism
Signal Transduction
Surface Plasmon Resonance
Transforming Growth Factor alpha - pharmacology
Title Epidermal Growth Factor Receptor Dimerization and Activation Require Ligand-Induced Conformational Changes in the Dimer Interface
URI http://mcb.asm.org/content/25/17/7734.abstract
https://www.tandfonline.com/doi/abs/10.1128/MCB.25.17.7734-7742.2005
https://www.ncbi.nlm.nih.gov/pubmed/16107719
https://search.proquest.com/docview/68495058
https://pubmed.ncbi.nlm.nih.gov/PMC1190273
Volume 25
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