National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01GM136976
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35GM142937
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2023 タイトル: Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor. 著者: Liwei Wang / Catherine Hall / Jie Li / Eunhee Choi / Xiao-Chen Bai / 要旨: 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.
解像度のタイプ: BY AUTHOR / 解像度: 3.4 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION / 使用した粒子像数: 79010
初期 角度割当
タイプ: PROJECTION MATCHING / ソフトウェア - 名称: RELION
最終 角度割当
タイプ: PROJECTION MATCHING / ソフトウェア - 名称: RELION
最終 3次元分類
ソフトウェア - 名称: RELION
-
原子モデル構築 1
精密化
空間: REAL / プロトコル: AB INITIO MODEL
得られたモデル
PDB-7tym: Cryo-EM Structure of insulin receptor-related receptor (IRR) in active-state captured at pH 9. The 3D refinement was applied with C2 symmetry