title: Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family.
abstract: 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.
authors.affiliation: D. E. Shaw Research , New York , United States.
authors.forename: Anton
authors.initials: A
authors.lastname: Arkhipov
authors.forename: Yibing
authors.initials: Y
authors.lastname: Shan
authors.forename: Eric T
authors.initials: ET
authors.lastname: Kim
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Her2/ErbB2 activation; None; dimerization interface; extracellular domain conformation