title: Engineering Small Molecule Responsive Split Protein Kinases.
abstract: The over 500 human protein kinases are estimated to phosphorylate at least one-third of the proteome. This posttranslational modification is of paramount importance to intracellular signaling and its deregulation is linked to numerous diseases. Deciphering the specific cellular role of a protein kinase of interest remains challenging given their structural similarity and potentially overlapping activity. In order to exert control over the activity of user-defined kinases and allow for understanding and engineering of complex signal transduction pathways, we have designed ligand inducible split protein kinases. In this approach, protein kinases are dissected into two fragments that cannot spontaneously assemble and are thus inactive. The two kinase fragments are attached to chemical inducers of dimerization (CIDs) that allow for ligand induced heterodimerization and concomitant activation of kinase activity.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, 1306 East University Boulevard, Tucson, AZ, 85721, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Castillo-Montoya
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, 1306 East University Boulevard, Tucson, AZ, 85721, USA. ghosh@email.arizona.edu.
authors.forename: Indraneel
authors.initials: I
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D002460:Cell Line; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D010766:Phosphorylation / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology; D054852:Small Molecule Libraries / Q000378:metabolism*
chemical_list: D008024:Ligands; D054852:Small Molecule Libraries; D011494:Protein Kinases
keywords: Chemical inducer of dimerization; Ligand gating; Protein kinase; Split kinase; Split protein