Insulin and epidermal growth factor receptor family members share parallel activation mechanisms.

Insulin receptor (IR) and the epidermal growth factor receptor (EGFR) were the first receptor tyrosine kinases (RTKs) to be studied in detail. Both are important clinical targets-in diabetes and cancer, respectively. They have unique extracellular domain compositions among RTKs, but share a common module with two ligand-binding leucine-rich-repeat (LRR)-like domains connected by a flexible cysteine-rich (CR) domain (L1-CR-L2 in IR/domain, I-II-III in EGFR). This module is linked to the transmembrane region by three fibronectin type III domains in IR, and by a second CR in EGFR. Despite sharing this conserved ligand-binding module, IR and EGFR family members are considered mechanistically distinct-in part because IR is a disulfide-linked (αβ)2 dimer regardless of ligand binding, whereas EGFR is a monomer that undergoes ligand-induced dimerization. Recent cryo-electron microscopy (cryo-EM) structures suggest a way of unifying IR and EGFR activation mechanisms and origins of negative cooperativity. In EGFR, ligand engages both LRRs in the ligand-binding module, "closing" this module to break intramolecular autoinhibitory interactions and expose new dimerization sites for receptor activation. How insulin binds the activated IR was less clear until now. Insulin was known to associate with one LRR (L1), but recent cryo-EM structures suggest that it also engages the second LRR (albeit indirectly) to "close" the L1-CR-L2 module, paralleling EGFR. This transition simultaneously breaks autoinhibitory interactions and creates new receptor-receptor contacts-remodeling the IR dimer (rather than inducing dimerization per se) to activate it. Here, we develop this view in detail, drawing mechanistic links between IR and EGFR.