Using single-particle electron microscopy, research collaborators from two institutions were able to visualize insulin receptor for the first time in its activated and un-activated state. The conformational change that takes place when insulin binds to the cell-surface receptor had been poorly understood. This new study, published in the Journal of Cell Biology, provides the groundwork for further studies on insulin receptor regulation and for testing new drug therapies for insulin-related diseases.
Insulin is a hormone that has a key role in metabolism regulation. Insulin binds to insulin receptor which is located on the plasma membrane of most mammalian cells. In order to study the conformational change that happens upon insulin receptor activation, the research team used artificial plasma membrane patches, or nanodiscs, embedded with purified full-length insulin receptor protein. The membranes holding the receptors could be visualized using single-particle electron microscopy, an advanced imaging technique. "This technology enables us to directly study the cell-surface receptors in an artificial membrane environment", explains Dr. Ünal Coskun, group leader at IPI/PLID and co-senior author of the study.
The images illustrated that the receptor made a significant conformational change from a U-shape to a T-shape upon activation with insulin. This rearrangement brings the two primary domains together which most likely influences kinase domain interactions that activate the signaling cascade within the cell. The study provides a deeper understanding of the mechanism by which insulin activates its receptor which could lead to better treatments for diabetes and other metabolic disorders.
Image: How the insulin receptor works. Image courtesy of Gutmann et al. 2018.