7TYJ

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

Summary for 7TYJ

• Entry DOI: 10.2210/pdb7tyj/pdb
• EMDB information: 26181
• Descriptor: Insulin receptor-related protein (1 entity in total)
• Functional Keywords: receptor tyrosine kinase, insulin receptor family, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 287759.09

Authors

Wang, L.W.,Hall, C.,Li, J.,Choi, E.,Bai, X.C. (deposition date: 2022-02-13, release date: 2023-02-15, Last modification date: 2024-10-16)

Primary citation

Wang, L.,Hall, C.,Li, J.,Choi, E.,Bai, X.C.
Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor.
Nat.Struct.Mol.Biol., 30:661-669, 2023

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 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.

PubMed: 37055497
DOI: 10.1038/s41594-023-00974-0

Experimental method

ELECTRON MICROSCOPY (3.3 Å)