Engineering FKBP-Based Destabilizing Domains to Build Sophisticated Protein Regulation Systems

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 succe...

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Bibliographic Details
Published in:PloS one 2015-12, Vol.10 (12), p.e0145783
Main Authors: An, Wenlin, Jackson, Rachel E, Hunter, Paul, Gögel, Stefanie, van Diepen, Michiel, Liu, Karen, Meyer, Martin P, Eickholt, Britta J
Format: Article
Language:English
Subjects:
Animal models
Animals
Biochemistry
Cell cycle
Cell Line, Tumor
Cloning
Consolidation
Control
Control stability
Control systems
Electrostatic properties
Epitopes
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Humans
Kinases
Ligands
Neurobiology
Neurosciences
Penicillin
Phosphatase
Protein Stability - drug effects
Protein Structure, Tertiary
Proteins
PTEN protein
Small Molecule Libraries - pharmacology
System effectiveness
Tacrolimus Binding Proteins - genetics
Tacrolimus-binding protein
Tagging
Tumor suppressor genes
Zebrafish
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0145783