Faculty, Staff and Student Publications
Language
English
Publication Date
5-1-2023
Journal
Nature Structural & Molecular Biology
DOI
10.1038/s41594-023-00974-0
PMID
37055497
PMCID
PMC10465182
PubMedCentral® Posted Date
8-29-2023
PubMedCentral® Full Text Version
Author MSS
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 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.
Keywords
Humans, Receptor, Insulin, Hydrogen-Ion Concentration, Insulin
Published Open-Access
yes
Recommended Citation
Wang, Liwei; Hall, Catherine; Li, Jie; et al., "Structural Basis of the Alkaline pH-Dependent Activation of Insulin Receptor-Related Receptor" (2023). Faculty, Staff and Student Publications. 787.
https://digitalcommons.library.tmc.edu/uthshis_docs/787