Transformation of Receptor Tyrosine Kinases into Glutamate Receptors and Photoreceptors. Issue 17 (4th March 2020)

• Record Type: Journal Article
• Authors: Leippe, Philipp; Broichhagen, Johannes; Cailliau, Katia; Mougel, Alexandra; Morel, Marion; Dissous, Colette; Trauner, Dirk; Vicogne, Jérôme
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 17(2020)
• Page Start: 6720
• Page End: 6723
• Publication Date: 2020-03-04
• Subjects: photopharmacology -- receptor tyrosine kinases -- signal transduction -- synthetic biology -- Venus kinase receptors; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201915352
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Receptor tyrosine kinases (RTKs) are key regulators of cellular functions in metazoans. In vertebrates, RTKs are mostly activated by polypeptides but are not naturally sensitive to amino acids or light. Taking inspiration from Venus kinase receptors (VKRs), an atypical family of RTKs found in nature, we have transformed the human insulin (hIR) and hepatocyte growth factor receptor (hMET) into glutamate receptors by replacing their extracellular binding domains with the ligand‐binding domain of metabotropic glutamate receptor type 2 (mGluR2). We then imparted light sensitivity through covalent attachment of a synthetic glutamate‐based photoswitch via a self‐labelling SNAP tag. By employing a Xenopus laevis oocyte kinase activity assay, we demonstrate how these chimeric RTKs, termed light‐controlled human insulin receptor (LihIR) and light‐controlled human MET receptor (LihMET), can be used to exert optical control over the insulin or MET signaling pathways. Our results outline a potentially general strategy to convert RTKs into photoreceptors. Abstract : Optical Umami : Through a combination of protein engineering and chemical synthesis, the human insulin receptor, a receptor tyrosine kinase (RTK), was converted into a glutamate (red) receptor and then a photoreceptor. The resulting chimeric RTK (grey) can be used to exert optical control over the insulin signaling pathway. The same approach was also applied to the hepatocyte growth factor receptor.