A novel view of the insulin signaling pathway based on prediction of protein structure by the AI platform AlphaFold

Abstract

Recent advances in artificial intelligence (AI) are rapidly affecting many aspects of daily life. This new technology has also had a large impact on life science research. In particular, in fields that deal with massive data setssuch as genomics, imaging, and real-world clinical research -AI is contributing to the diagnosis of or the risk prediction for various diseases as well as to the development of new treatments. One major achievement of AI technology is the prediction of protein folding. Alphafold2, an AI system developed by DeepMind, has revolutionized the field of protein structure by predicting the three-dimensional architecture of a given protein from only its amino acid sequence with a high level of accuracy 1,2 .Proteins were long thought to exert their functions in a manner dependent on regions with 'rigid' structures. Regions with no defined secondary or tertiary structure, sometimes termed intrinsically disordered regions (IDRs), were thus thought to serve merely as intrinsic connectors of the functional domains 3 . However, it is now clear that, similar to regions with rigid structures, IDRs are subject to various posttranslational modifications, interact with other molecules, and play pivotal roles in protein function 3 .Signaling initiated by the insulin receptor is one of the most extensively studied intracellular signaling pathways (Figure 1). Binding of insulin to its receptor triggers robust stimulation of the intrinsic tyrosine kinase activity of the receptor and the consequent phosphorylation of insulin receptor substrate (IRS) on tyrosine residues 4,5 . Phosphorylated IRS then binds to other signaling proteins including phosphatidylinositol 3-kinase (PI3K), which consists of both regulatory and catalytic subunits, as well as the adapter protein Grb2, with the latter interaction leading to activation of the Ras-MAPK (mitogen-activated protein kinase) pathway 4,5 . The association of IRS with the regulatory subunit of PI3K and Grb2 is mediated by SH2 (Src homology 2) domains of the latter proteins. The binding of IRS to PI3K results in the activation of the lipid kinase and the consequent generation of phosphatidylinositol 3,4,5trisphosphate (PIP 3 ), which in turn activates the serine-threonine kinase PDK1 (3-phosphoinositide-dependent kinase 1) 4,5 .