Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Originally published in Science Express on 1 August 2002
Science 23 August 2002:
Vol. 297. no. 5585, pp. 1330 - 1333
DOI: 10.1126/science.1074611
Prev | Table of Contents | Next

Reports

Structure of the Extracellular Region of HER3 Reveals an Interdomain Tether

Hyun-Soo Cho, Daniel J. Leahy*

We have determined the 2.6 angstrom crystal structure of the entire extracellular region of human HER3 (ErbB3), a member of the epidermal growth factor receptor (EGFR) family. The structure consists of four domains with structural homology to domains found in the type I insulin-like growth factor receptor. The HER3 structure reveals a contact between domains II and IV that constrains the relative orientations of ligand-binding domains and provides a structural basis for understanding both multiple-affinity forms of EGFRs and conformational changes induced in the receptor by ligand binding during signaling. These results also suggest new therapeutic approaches to modulating the behavior of members of the EGFR family.

Department of Biophysics and Biophysical Chemistry, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
*   To whom correspondence should be addressed. E-mail: leahy{at}groucho.med.jhmi.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Oncogenic EGFR Signaling Networks in Glioma.
P. H. Huang, A. M. Xu, and F. M. White (2009)
Science Signaling 2, re6
   Abstract »    Full Text »    PDF »
Homodimerization Controls the Fibroblast Growth Factor 9 Subfamily's Receptor Binding and Heparan Sulfate-Dependent Diffusion in the Extracellular Matrix.
J. Kalinina, S. A. Byron, H. P. Makarenkova, S. K. Olsen, A. V. Eliseenkova, W. J. Larochelle, M. Dhanabal, S. Blais, D. M. Ornitz, L. A. Day, et al. (2009)
Mol. Cell. Biol. 29, 4663-4678
   Abstract »    Full Text »    PDF »
All EGF(ErbB) receptors have preformed homo- and heterodimeric structures in living cells.
R.-H. Tao and I. N. Maruyama (2008)
J. Cell Sci. 121, 3207-3217
   Abstract »    Full Text »    PDF »
Mutational Activation of ErbB2 Reveals a New Protein Kinase Autoinhibition Mechanism.
Y.-X. Fan, L. Wong, J. Ding, N. A. Spiridonov, R. C. Johnson, and G. R. Johnson (2008)
J. Biol. Chem. 283, 1588-1596
   Abstract »    Full Text »    PDF »
Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib.
T. M. Gilmer, L. Cable, K. Alligood, D. Rusnak, G. Spehar, K. T. Gallagher, E. Woldu, H. L. Carter, A. T. Truesdale, L. Shewchuk, et al. (2008)
Cancer Res. 68, 571-579
   Abstract »    Full Text »    PDF »
Targeting Human Epidermal Growth Factor Receptor 2: It Is Time to Kill Kinase Death Human Epidermal Growth Factor Receptor 3.
J. A. Menendez and R. Lupu (2007)
J. Clin. Oncol. 25, 2496-2498
   Full Text »    PDF »
The Asn418-Linked N-Glycan of ErbB3 Plays a Crucial Role in Preventing Spontaneous Heterodimerization and Tumor Promotion.
S. Yokoe, M. Takahashi, M. Asahi, S. H. Lee, W. Li, D. Osumi, E. Miyoshi, and N. Taniguchi (2007)
Cancer Res. 67, 1935-1942
   Abstract »    Full Text »    PDF »
Targeting HER2 in Prostate Cancer: Where to Next?.
D. B. Solit and N. Rosen (2007)
J. Clin. Oncol. 25, 241-243
   Full Text »    PDF »
The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand.
S. Bouyain, P. A. Longo, S. Li, K. M. Ferguson, and D. J. Leahy (2005)
PNAS 102, 15024-15029
   Abstract »    Full Text »    PDF »
Epidermal Growth Factor Receptor Dimerization and Activation Require Ligand-Induced Conformational Changes in the Dimer Interface.
J. P. Dawson, M. B. Berger, C.-C. Lin, J. Schlessinger, M. A. Lemmon, and K. M. Ferguson (2005)
Mol. Cell. Biol. 25, 7734-7742
   Abstract »    Full Text »    PDF »
Ligand-induced Dimer-Tetramer Transition during the Activation of the Cell Surface Epidermal Growth Factor Receptor-A Multidimensional Microscopy Analysis.
A. H. A. Clayton, F. Walker, S. G. Orchard, C. Henderson, D. Fuchs, J. Rothacker, E. C. Nice, and A. W. Burgess (2005)
J. Biol. Chem. 280, 30392-30399
   Abstract »    Full Text »    PDF »
The epidermal growth factor receptor family.
L A Bazley and W J Gullick (2005)
Endocr. Relat. Cancer 12, S17-S27
   Abstract »    Full Text »    PDF »
A Structural Model for the Membrane-bound Form of the Juxtamembrane Domain of the Epidermal Growth Factor Receptor.
K. Choowongkomon, C. R. Carlin, and F. D. Sonnichsen (2005)
J. Biol. Chem. 280, 24043-24052
   Abstract »    Full Text »    PDF »
Oligomers of ERBB3 Have Two Distinct Interfaces That Differ in Their Sensitivity to Disruption by Heregulin.
K. Kani, C. M. Warren, C. S. Kaddis, J. A. Loo, and R. Landgraf (2005)
J. Biol. Chem. 280, 8238-8247
   Abstract »    Full Text »    PDF »
Targeting ErbB receptor signaling: A pan-ErbB approach to cancer.
C. D. Britten (2004)
Mol. Cancer Ther. 3, 1335-1342
   Abstract »    Full Text »    PDF »
Identification of the Epitope for the Epidermal Growth Factor Receptor-specific Monoclonal Antibody 806 Reveals That It Preferentially Recognizes an Untethered Form of the Receptor.
T. G. Johns, T. E. Adams, J. R. Cochran, N. E Hall, P. A. Hoyne, M. J. Olsen, Y.-S. Kim, J. Rothacker, E. C. Nice, F. Walker, et al. (2004)
J. Biol. Chem. 279, 30375-30384
   Abstract »    Full Text »    PDF »
CR1/CR2 Interactions Modulate the Functions of the Cell Surface Epidermal Growth Factor Receptor.
F. Walker, S. G. Orchard, R. N. Jorissen, N. E. Hall, H.-H. Zhang, P. A. Hoyne, T. E. Adams, T. G. Johns, C. Ward, T. P. J. Garrett, et al. (2004)
J. Biol. Chem. 279, 22387-22398
   Abstract »    Full Text »    PDF »
Mechanistic Diversity of Cytokine Receptor Signaling Across Cell Membranes.
R. M. Stroud and J. A. Wells (2004)
Sci. STKE 2004, re7
   Abstract »    Full Text »    PDF »
The tethered configuration of the EGF receptor extracellular domain exerts only a limited control of receptor function.
D. Mattoon, P. Klein, M. A. Lemmon, I. Lax, and J. Schlessinger (2004)
PNAS 101, 923-928
   Abstract »    Full Text »    PDF »
A structure-based model for ligand binding and dimerization of EGF receptors.
P. Klein, D. Mattoon, M. A. Lemmon, and J. Schlessinger (2004)
PNAS 101, 929-934
   Abstract »    Full Text »    PDF »
Structural Analysis of an Epidermal Growth Factor/Transforming Growth Factor-{alpha} Chimera with Unique ErbB Binding Specificity.
M. Wingens, T. Walma, H. van Ingen, C. Stortelers, J. E. M. van Leeuwen, E. J. J. van Zoelen, and G. W. Vuister (2003)
J. Biol. Chem. 278, 39114-39123
   Abstract »    Full Text »    PDF »
Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET.
S. Kjaer and C. F. Ibanez (2003)
Hum. Mol. Genet. 12, 2133-2144
   Abstract »    Full Text »    PDF »
Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3.
C.-h. B. Chen, G. A. Chernis, V. Q. Hoang, and R. Landgraf (2003)
PNAS 100, 9226-9231
   Abstract »    Full Text »    PDF »
Selective Formation of ErbB-2/ErbB-3 Heterodimers Depends on the ErbB-3 Affinity of Epidermal Growth Factor-like Ligands.
C. Stortelers, S. P. van der Woning, S. Jacobs-Oomen, M. Wingens, and E. J. J. van Zoelen (2003)
J. Biol. Chem. 278, 12055-12063
   Abstract »    Full Text »    PDF »
Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand.
B.-H. Luo, T. A. Springer, and J. Takagi (2003)
PNAS 100, 2403-2408
   Abstract »    Full Text »    PDF »
Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor.
J. Stamos, M. X. Sliwkowski, and C. Eigenbrot (2002)
J. Biol. Chem. 277, 46265-46272
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)