Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family

The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodime...

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Bibliographic Details
Published in:eLife 2013-07, Vol.2, p.e00708-e00708
Main Authors: Arkhipov, Anton, Shan, Yibing, Kim, Eric T, Dror, Ron O, Shaw, David E
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Biophysics and Structural Biology
Conformation
Crystal structure
Dimerization
dimerization interface
Epidermal growth factor
Epidermal growth factor receptors
ErbB-2 protein
extracellular domain conformation
Her2/ErbB2 activation
Humans
Kinases
Ligands
Molecular Sequence Data
Preservation
Protein-tyrosine kinase receptors
Receptor, Epidermal Growth Factor - chemistry
Receptor, Epidermal Growth Factor - metabolism
Receptor, ErbB-2 - chemistry
Receptor, ErbB-2 - metabolism
Sequence Homology, Amino Acid
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Summary:The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodimerization, however, remains poorly understood. The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric. Here, we report results from long-timescale molecular dynamics simulations indicating that a single ligand is necessary and sufficient to stabilize the ectodomain interface of Her2 heterodimers, which assume an asymmetric conformation similar to that of dEGFR dimers. This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human. DOI:http://dx.doi.org/10.7554/eLife.00708.001.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.00708