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| Title | Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Vol. 30, Issue 5, Page 661-669, Year 2023 |
| Publish date | Apr 13, 2023 |
 Authors | Liwei Wang / Catherine Hall / Jie Li / Eunhee Choi / Xiao-Chen Bai /  |
| PubMed Abstract | 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 ...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. |
 External links | Nat Struct Mol Biol / PubMed:37055497 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.3 - 3.5 Å |
| Structure data | EMDB-26181, PDB-7tyj: EMDB-26183, PDB-7tyk: EMDB-26185, PDB-7tym: |
| Source |
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 Keywords |  SIGNALING PROTEIN / Receptor tyrosine kinase / insulin receptor family |
