TY - JOUR
T1 - Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor
AU - Wang, Liwei
AU - Hall, Catherine
AU - Li, Jie
AU - Choi, Eunhee
AU - Bai, Xiao chen
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s41594-023-00974-0
DO - 10.1038/s41594-023-00974-0
M3 - Article
C2 - 37055497
AN - SCOPUS:85152697482
SN - 1545-9993
VL - 30
SP - 661
EP - 669
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 5
ER -