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Cryo-EM Structure of insulin receptor-related receptor (IRR) in apo-state captured at pH 7. The 3D refinement was focused on one of two halves with C1 symmetry applied
Structural highlights
FunctionINSRR_HUMAN Receptor with tyrosine-protein kinase activity. Functions as a pH sensing receptor which is activated by increased extracellular pH. Activates an intracellular signaling pathway that involves IRS1 and AKT1/PKB.[1] Publication Abstract from PubMedThe 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. Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor.,Wang L, Hall C, Li J, Choi E, Bai XC Nat Struct Mol Biol. 2023 May;30(5):661-669. doi: 10.1038/s41594-023-00974-0. , Epub 2023 Apr 13. PMID:37055497[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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