Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 5, Pages 1646-1651Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1215207110
Keywords
EGF receptor; HER2 receptor; PIP2
Categories
Funding
- Naito Foundation
- National Institutes of Health [GM 46732]
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The transmembrane (TM) and juxtamembrane (JM) regions of the ErbB family receptor tyrosine kinases connect the extracellular ligand-binding domain to the intracellular kinase domain. Evidence for the role of these regions in the mechanism of receptor dimerization and activation is provided by TM-JM peptides corresponding to the Neu (or rat ErbB2) receptor. Solid-state NMR and fluorescence spectroscopy show that there are tight interactions of the JM sequence with negatively charged lipids, including phosphatidylinositol 4,5-bisphosphate, in TM-JM peptides corresponding to the wildtype receptor sequence. We observe a release of the JM sequence from the negatively charged membrane surface using peptides containing an activating V664E mutation within the TM domain or in peptides engineered to form TM helix dimers with Va1664 in the interface. These results provide the basis of a mechanism for coupling ligand binding to kinase activation in the full-length receptor.
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