Title :
EGF activates its receptor by removing interactions that autoinhibit ectodomain
dimerization
Abstract :
- Epidermal growth factor (EGF) receptor is the prototype of the ErbB ( HER ) family receptor tyrosine kinases (RTKs), which regulate cell growth and differentiation and are implicated in many human cancers
- EGF activates its receptor by inducing dimerization of the 621 amino acid EGF receptor extracellular region
- We describe the 2.8 A resolution crystal structure of this entire extracellular region (sEGFR) in an unactivated state
- The structure reveals an autoinhibited configuration, where the dimerization interface recently identified in activated sEGFR structures is completely occluded by intramolecular interactions
- To activate the receptor, EGF binding must promote a large domain rearrangement that exposes this dimerization interface
- This contrasts starkly with other RTK activation mechanisms and suggests new approaches for designing ErbB receptor antagonists
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