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Insulin and epidermal growth factor receptor family members share parallel activation mechanisms
Kathryn M Ferguson1, Chun Hu1, Mark A Lemmon1
1Department of Pharmacology and Cancer Biology Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
Abstract:
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.
Insights
Insulin receptor (IR) and epidermal growth factor receptor (EGFR) activation mechanisms are unified by recent cryo-electron microscopy (cryo-EM) structures. Both receptors utilize ligand binding to "close" their extracellular domains, breaking autoinhibitory interactions and initiating signaling pathways.
Area of Science:
- Molecular and Cellular Biology
- Structural Biology
- Biochemistry
Background:
- Insulin receptor (IR) and epidermal growth factor receptor (EGFR) are key receptor tyrosine kinases (RTKs) targeted in diabetes and cancer, respectively.
- Both RTKs possess unique extracellular domain compositions but share a conserved ligand-binding module comprising leucine-rich-repeat (LRR)-like domains.
- Mechanistic distinctions exist: IR is a constitutive dimer, while EGFR is a monomer requiring ligand-induced dimerization for activation.
Purpose of the Study:
- To unify the activation mechanisms of the insulin receptor (IR) and epidermal growth factor receptor (EGFR).
- To elucidate the role of ligand binding in breaking autoinhibitory interactions and promoting receptor activation in both IR and EGFR.
- To explore the origins of negative cooperativity in RTK signaling.
Main Methods:
- Analysis of recent cryo-electron microscopy (cryo-EM) structures of IR and EGFR.
- Comparative analysis of ligand-binding interactions within the conserved extracellular domain module.
- Mechanistic modeling of receptor conformational changes upon ligand engagement.
Main Results:
- Cryo-EM structures reveal that ligand binding to both IR and EGFR causes a "closing" of their respective L1-CR-L2 (IR) or domain I-II-III (EGFR) modules.
- This "closing" event breaks intramolecular autoinhibitory interactions within each receptor.
- For IR, "closing" remodels the existing dimer for activation; for EGFR, it exposes dimerization sites, paralleling activation mechanisms.
Conclusions:
- A unified model for IR and EGFR activation is proposed, centered on ligand-induced "closing" of the extracellular ligand-binding module.
- This mechanism explains how distinct RTKs utilize conserved structural elements to initiate signaling.
- The findings provide mechanistic links between IR and EGFR activation, offering insights into RTK evolution and negative cooperativity.
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