Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor

The authors solve cryo-EM structures of the alkaline pH-induced insulin receptor-related receptor (IRR), providing clues into its activation mechanism by pH. The insulin receptor (IR) family is a subfamily of receptor tyrosine kinases that controls metabolic homeostasis and cell growth. Distinct from IR and insulin-like growth factor 1 receptor, whose activation requires ligand binding, insulin receptor-related receptor (IRR)-the third member of the IR family-is activated by alkaline pH. However, the molecular mechanism underlying alkaline pH-induced IRR activation remains unclear. Here, we present cryo-EM structures of human IRR in both neutral pH inactive and alkaline pH active states. Combined with mutagenesis and cellular assays, we show that, upon pH increase, electrostatic repulsion of the pH-sensitive motifs of IRR disrupts its autoinhibited state and promotes a scissor-like rotation between two protomers, leading to a T-shaped active conformation. Together, our study reveals an unprecedented alkaline pH-dependent activation mechanism of IRR, opening up opportunities to understand the structure-function relationship of this important receptor.

Automated summary

The authors used cryo-EM to determine the structures of alkaline pH-induced insulin receptor-related receptor (IRR), revealing the mechanism of IRR activation by pH. Unlike other members of the insulin receptor family, IRR is activated by alkaline pH instead of ligand binding. Through mutagenesis and cellular assays, it was shown that the repulsion of pH-sensitive motifs disrupts the autoinhibited state of IRR and leads to a T-shaped active conformation. This study uncovers a novel pH-dependent activation mechanism of IRR, providing insights into its structure-function relationship.