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Mol Cell Biol. 2010 Nov;30(22):5432-43. doi: 10.1128/MCB.00742-10. Epub 2010 Sep 13.

Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor.

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  • 1Immune Disease Institute and Department of Pathology, Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USA.

Abstract

The mechanisms by which signals are transmitted across the plasma membrane to regulate signaling are largely unknown for receptors with single-pass transmembrane domains such as the epidermal growth factor receptor (EGFR). A crystal structure of the extracellular domain of EGFR dimerized by epidermal growth factor (EGF) reveals the extended, rod-like domain IV and a small, hydrophobic domain IV interface compatible with flexibility. The crystal structure and disulfide cross-linking suggest that the 7-residue linker between the extracellular and transmembrane domains is flexible. Disulfide cross-linking of the transmembrane domain shows that EGF stimulates only moderate association in the first two α-helical turns, in contrast to association throughout the membrane over five α-helical turns in glycophorin A and integrin. Furthermore, systematic mutagenesis to leucine and phenylalanine suggests that no specific transmembrane interfaces are required for EGFR kinase activation. These results suggest that linkage between ligand-induced dimerization and tyrosine kinase activation is much looser than was previously envisioned.

PMID:
20837704
[PubMed - indexed for MEDLINE]
PMCID:
PMC2976375
Free PMC Article
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