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The researchers from the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital Carl Gustav Carus of TU Dresden together with colleagues from Rockefeller University New York succeeded for the first time in the visualization of the insulin receptor activation.
Insulin exerts multiple effects on cellular metabolism and growth. The biological actions of insulin are mediated by a cell-surface receptor, called insulin receptor, which is present on the surface, i.e. the plasma membrane, of virtually all mammalian cells. The dysfunction of insulin receptor has been linked to severe pathologies including diabetes mellitus or cancer. Insulin binds outside the cell to the extracellular domain of its receptor and induces a structural change that is propagated across the membrane to the intracellular kinase domains inside the cell, causing them to activate each other, thus initiating signaling cascades.
The nature of this structural change remained a mystery for decades, resulting in mutually exclusive models for insulin receptor activation being put forward. To obtain insights into receptor activation, researchers purified full-length insulin receptors and embedded them into nanodiscs, which are nanoscale disc-shaped membrane patches. Those could then be directly visualized by single-particle electron microscopy.
This technology enables researchers to directly study the cell-surface receptors in an artificial membrane environment. In the absence of insulin, the receptor displays an inverted U-shaped ectodomain, which is consistent with previous crystallographic studies of isolated ectodomains, implying that the membrane-passing transmembrane domains and thus kinase domains are held well apart from each other. Upon insulin binding, the ectodomain of the receptor undergoes a dramatic reorganization, changing from a U-shaped to a T-shaped structure and also causing a rearrangement of the transmembrane domains. These now come together likely facilitating kinase domain interactions and thus their activation.
These nanodisc-embedded receptors provide a novel platform to address further questions regarding insulin receptor regulation and eventually to test therapeutic agents. The results directly demonstrate the structural transition in the full-length receptor upon insulin binding and offer an answer to the longstanding question concerning the mechanism by which insulin activates its receptor, thus improving understanding of the receptor.
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