The Activation Mechanism of the Insulin Receptor: A Structural Perspective

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.

Automated summary

The insulin receptor (IR) is a type II receptor tyrosine kinase that plays crucial roles in metabolism, growth, and proliferation. Recent advances in cryo-electron microscopy have allowed the determination of IR structures with different numbers of bound insulin molecules, providing important insights into the activation mechanism of this receptor. This review summarizes the insulin-induced activation mechanism of IR, including the binding modes and functions of insulin at different sites, as well as the structural transitions necessary for IR activation. It also highlights key aspects of IR signaling activation and regulation and suggests future research directions to fill the remaining gaps in our understanding.