The role of kinase domain dimerization in EGFR activation.

ABSTRACT: The epidermal growth factor receptor (EGFR) was among the first receptor tyrosine kinases (RTKs) shown to be activated by ligand-induced dimerization. Structural studies explain how ligand binding induces the dimerization of EGFR's extracellular region. Unlike other RTKs, EGFR's intracellular tyrosine kinase domain (TKD) is activated allosterically in an asymmetric dimer that is observed crystallographically, but not in cryo-EM studies of intact EGFR. Here, we show that this asymmetric TKD dimer forms only transiently - explaining its lack of definition by cryo-EM. By engineering an asymmetric TKD dimer and studying a TKD-duplicated lung cancer EGFR variant, we show that TKD dimerization increases kinase activity by several hundred-fold. We were also able to stabilize and visualize discret

SUBMITTER: Petrova ZO 

PROVIDER: S-EPMC12731945 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature