The EGF receptor kinase domain is strongly activated by weak dimerization

The tyrosine kinase domain (TKD) of the epidermal growth factor receptor (EGFR) activates via a unique mechanism of asymmetric dimerization with a partner EGFR TKD rather than a more typical mechanism of activation loop phosphorylation. There is an EGFR oncogenic variant found in patients in which the TKD region of EGFR has been duplicated, resulting in a construct in which two EGFR kinase domain are linked via a natural peptide linker (KDD). KDD is the best approximation of the natural process of EGFR kinase dimerization and activation as well as an example of bona fide oncogenic activation. We studied the structure, enzyme properties, and structural dynamics of KDD to gather insights into the EGFR kinase activation process and its oncogenicity.