Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 30, Issue 22, Pages 5432-5443Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00742-10
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Funding
- American Cancer Society [PF-07-055-01-GMC]
- NIH [HL-48675]
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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 alpha-helical turns, in contrast to association throughout the membrane over five alpha-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.
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