Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor. Mol Cell Biol 2010 Nov;30(22):5432-43
Date
09/15/2010Pubmed ID
20837704Pubmed Central ID
PMC2976375DOI
10.1128/MCB.00742-10Scopus ID
2-s2.0-78649548465 (requires institutional sign-in at Scopus site) 178 CitationsAbstract
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.
Author List
Lu C, Mi LZ, Grey MJ, Zhu J, Graef E, Yokoyama S, Springer TAAuthor
Jieqing Zhu PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceCell Line
Cross-Linking Reagents
Cysteine
Dimerization
Disulfides
Enzyme Activation
ErbB Receptors
Humans
Ligands
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Structure, Quaternary
Protein Structure, Secondary
Sequence Alignment
Signal Transduction
X-Ray Diffraction
