title: Engineering FKBP-Based Destabilizing Domains to Build Sophisticated Protein Regulation Systems.
abstract: Targeting protein stability with small molecules has emerged as an effective tool to control protein abundance in a fast, scalable and reversible manner. The technique involves tagging a protein of interest (POI) with a destabilizing domain (DD) specifically controlled by a small molecule. The successful construction of such fusion proteins may, however, be limited by functional interference of the DD epitope with electrostatic interactions required for full biological function of proteins. Another drawback of this approach is the remaining endogenous protein. Here, we combined the Cre-LoxP system with an advanced DD and generated a protein regulation system in which the loss of an endogenous protein, in our case the tumor suppressor PTEN, can be coupled directly with a conditionally fine-tunable DD-PTEN. This new system will consolidate and extend the use of DD-technology to control protein function precisely in living cells and animal models.
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, United Kingdom.|Charité - Universitätsmedizin Berlin, Cluster of Excellence NeuroCure and Institute of Biochemistry, Berlin, 10117, Germany.
authors.forename: Wenlin
authors.initials: W
authors.lastname: An
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Jackson
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Hunter
authors.affiliation: Charité - Universitätsmedizin Berlin, Cluster of Excellence NeuroCure and Institute of Biochemistry, Berlin, 10117, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gögel
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Michiel
authors.initials: M
authors.lastname: van Diepen
authors.affiliation: Department of Craniofacial Development, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Liu
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, United Kingdom.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Meyer
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, London, SE1 1UL, United Kingdom.|Charité - Universitätsmedizin Berlin, Cluster of Excellence NeuroCure and Institute of Biochemistry, Berlin, 10117, Germany.
authors.forename: Britta J
authors.initials: BJ
authors.lastname: Eickholt
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D055550:Protein Stability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000235:genetics*; D015027:Zebrafish
chemical_list: D054852:Small Molecule Libraries; D022021:Tacrolimus Binding Proteins