TY - JOUR
T1 - The Activation Mechanism of the Insulin Receptor
T2 - A Structural Perspective
AU - Choi, Eunhee
AU - Bai, Xiao Chen
N1 - Publisher Copyright:
Copyright © 2023 by the author(s).
PY - 2023/6/20
Y1 - 2023/6/20
N2 - The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo-electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years, which have tremendously improved our understanding of how IR is activated by insulin. Here, we review the insulin-induced activation mechanism of IR, including (a) the detailed binding modes and functions of insulin at site 1 and site 2 and (b) the insulin-induced structural transitions that are required for IR activation. We highlight several other key aspects of the activation and regulation of IR signaling and discuss the remaining gaps in our understanding of the IR activation mechanism and potential avenues of future research.
AB - The insulin receptor (IR) is a type II receptor tyrosine kinase that plays essential roles in metabolism, growth, and proliferation. Dysregulation of IR signaling is linked to many human diseases, such as diabetes and cancers. The resolution revolution in cryo-electron microscopy has led to the determination of several structures of IR with different numbers of bound insulin molecules in recent years, which have tremendously improved our understanding of how IR is activated by insulin. Here, we review the insulin-induced activation mechanism of IR, including (a) the detailed binding modes and functions of insulin at site 1 and site 2 and (b) the insulin-induced structural transitions that are required for IR activation. We highlight several other key aspects of the activation and regulation of IR signaling and discuss the remaining gaps in our understanding of the IR activation mechanism and potential avenues of future research.
KW - activation mechanism
KW - cryo-EM
KW - insulin
KW - insulin receptor
KW - insulin-binding site 1
KW - insulin-binding site 2
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U2 - 10.1146/annurev-biochem-052521-033250
DO - 10.1146/annurev-biochem-052521-033250
M3 - Review article
C2 - 37001136
AN - SCOPUS:85163920246
SN - 0066-4154
VL - 92
SP - 247
EP - 272
JO - Annual review of biochemistry
JF - Annual review of biochemistry
ER -